Inhibitors of raf kinases

ABSTRACT

Provided herein are inhibitors of receptor tyrosine kinase effector, RAF, pharmaceutical compositions comprising said compounds, and methods for using said compounds for the treatment of diseases.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims benefit of U.S. Patent Application No.63/090,623 filed on Oct. 12, 2020, which is incorporated by reference inits entirety.

BACKGROUND

RAF kinase functions in the Ras-Raf-MEK-ERK mitogen activated proteinkinase (MAPK) pathway (also known as MAPK/ERK pathway) byphosphorylating and activating MEK. By altering the levels andactivities of transcription factors, MAPK leads to altered transcriptionof genes that are important for the cell cycle. Deregulation of MAPKactivity occurs frequently in tumors. Accordingly, therapies that targetRAF kinase activity are desired for use in the treatment of cancer andother disorders characterized by aberrant MAPK/ERK pathway signaling.

BRIEF SUMMARY OF THE INVENTION

Provided herein are inhibitors of the receptor tyrosine kinase effectorRaf (RAF), pharmaceutical compositions comprising said compounds, andmethods for using said compounds for the treatment of diseases.

One embodiment provides a compound, or pharmaceutically acceptable saltor solvate thereof, having the structure of Formula (I):

wherein,

-   -   X is N or C—H;    -   R¹ is selected from H, optionally substituted C1-C6 alkyl, or        optionally substituted C3-C7 cycloalkyl;    -   R² is selected from H, optionally substituted C1-C6 alkyl, or        optionally substituted C3-C7 cycloalkyl; or optionally, R¹ and        R² join to form a ring;    -   R³ is selected from H, —OH, —OR⁴, —NH₂, —NHR⁴, —N(R⁴)₂,        optionally substituted heterocyclyl, or optionally substituted        heteroaryl;    -   each R⁴ is independently selected from optionally substituted        C1-C6 alkyl, optionally substituted C1-C6 acyl or optionally, R²        and R⁴ join to form a ring; and    -   Z is an optionally substituted aryl or heteroaryl.

One embodiment provides a pharmaceutical composition comprising acompound of Formula (I), or pharmaceutically acceptable salt or solvatethereof, and at least one pharmaceutically acceptable excipient.

One embodiment provides a method of treating a disease or disorder in apatient in need thereof comprising administering to the patient acompound of Formula (I), or pharmaceutically acceptable salt or solvatethereof. Another embodiment provides the method wherein the disease ordisorder is cancer.

One embodiment provides a compound, or pharmaceutically acceptable saltor solvate thereof, having the structure of Formula (II):

wherein,

-   -   X is N or C—H;    -   R¹ is selected from H, optionally substituted C1-C6 alkyl, or        optionally substituted C3-C7 cycloalkyl;    -   R² is selected from H, optionally substituted C1-C6 alkyl, or        optionally substituted C3-C7 cycloalkyl; or optionally, R¹ and        R² join to form a ring;    -   R³ is selected from H, —OH, —OR⁴, —NH₂, —NHR⁴, —N(R⁴)₂,        optionally substituted heterocyclyl, or optionally substituted        heteroaryl;    -   each R⁴ is independently selected from optionally substituted        C1-C6 alkyl, optionally substituted C1-C6 acyl or optionally, R²        and R⁴ join to form a ring; and    -   Z is an optionally substituted aryl or heteroaryl.

One embodiment provides a pharmaceutical composition comprising acompound of Formula (II), or pharmaceutically acceptable salt or solvatethereof, and at least one pharmaceutically acceptable excipient.

One embodiment provides a method of treating a disease or disorder in apatient in need thereof comprising administering to the patient acompound of Formula (II), or pharmaceutically acceptable salt or solvatethereof. Another embodiment provides the method wherein the disease ordisorder is cancer.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference for the specificpurposes identified herein.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange, in some instances, will vary between 1% and 15% of the statednumber or numerical range. The term “comprising” (and related terms suchas “comprise” or “comprises” or “having” or “including”) is not intendedto exclude that in other certain embodiments, for example, an embodimentof any composition of matter, composition, method, or process, or thelike, described herein, “consist of” or “consist essentially of” thedescribed features.

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-Cisalkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₅alkyl). In other embodiments, an alkyl comprises one to four carbonatoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (e.g., C₁-C₃ alkyl). In other embodiments, analkyl comprises one to two carbon atoms (e.g., C₁-C₂ alkyl). In otherembodiments, an alkyl comprises one carbon atom (e.g., C₁ alkyl). Inother embodiments, an alkyl comprises five to fifteen carbon atoms(e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five toeight carbon atoms (e.g., C₅-C₈ alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In otherembodiments, an alkyl comprises three to five carbon atoms (e.g., C₃-C₅alkyl). In other embodiments, the alkyl group is selected from methyl,ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl(n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl isattached to the rest of the molecule by a single bond. Unless statedotherwise specifically in the specification, an alkyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl comprises two to six carbonatoms. In other embodiments, an alkynyl comprises two to four carbonatoms. The alkynyl is attached to the rest of the molecule by a singlebond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, andthe like. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group arethrough one carbon in the alkylene chain or through any two carbonswithin the chain. In certain embodiments, an alkylene comprises one toeight carbon atoms (e.g., C₁-C₈ alkylene). In other embodiments, analkylene comprises one to five carbon atoms (e.g., C₁-C₅ alkylene). Inother embodiments, an alkylene comprises one to four carbon atoms (e.g.,C₁-C₄ alkylene). In other embodiments, an alkylene comprises one tothree carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, analkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). Inother embodiments, an alkylene comprises one carbon atom (e.g., C₁alkylene). In other embodiments, an alkylene comprises five to eightcarbon atoms (e.g., C₅-C₈ alkylene). In other embodiments, an alkylenecomprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In otherembodiments, an alkylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkylene). Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onecarbon-carbon double bond, and having from two to twelve carbon atoms.The alkenylene chain is attached to the rest of the molecule through asingle bond and to the radical group through a single bond. In certainembodiments, an alkenylene comprises two to eight carbon atoms (e.g.,C₂-C₈ alkenylene). In other embodiments, an alkenylene comprises two tofive carbon atoms (e.g., C₂-C₅ alkenylene). In other embodiments, analkenylene comprises two to four carbon atoms (e.g., C₂-C₄ alkenylene).In other embodiments, an alkenylene comprises two to three carbon atoms(e.g., C₂-C₃ alkenylene). In other embodiments, an alkenylene comprisestwo carbon atoms (e.g., C₂ alkenylene). In other embodiments, analkenylene comprises five to eight carbon atoms (e.g., C₅-C₈alkenylene). In other embodiments, an alkenylene comprises three to fivecarbon atoms (e.g., C₃-C₅ alkenylene). Unless stated otherwisespecifically in the specification, an alkenylene chain is optionallysubstituted by one or more of the following substituents: halo, cyano,nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Alkynylene” or “alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onecarbon-carbon triple bond, and having from two to twelve carbon atoms.The alkynylene chain is attached to the rest of the molecule through asingle bond and to the radical group through a single bond. In certainembodiments, an alkynylene comprises two to eight carbon atoms (e.g.,C₂-C₈ alkynylene). In other embodiments, an alkynylene comprises two tofive carbon atoms (e.g., C₂-C₅ alkynylene). In other embodiments, analkynylene comprises two to four carbon atoms (e.g., C₂-C₄ alkynylene).In other embodiments, an alkynylene comprises two to three carbon atoms(e.g., C₂-C₃ alkynylene). In other embodiments, an alkynylene comprisestwo carbon atoms (e.g., C₂ alkynylene). In other embodiments, analkynylene comprises five to eight carbon atoms (e.g., C₅-C₈alkynylene). In other embodiments, an alkynylene comprises three to fivecarbon atoms (e.g., C₃-C₅ alkynylene). Unless stated otherwisespecifically in the specification, an alkynylene chain is optionallysubstituted by one or more of the following substituents: halo, cyano,nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of theformula —O—R^(c)-aryl where R^(c) is an alkylene chain as defined above,for example, methylene, ethylene, and the like. The alkylene chain partof the aralkyl radical is optionally substituted as described above foran alkylene chain. The aryl part of the aralkyl radical is optionallysubstituted as described above for an aryl group.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl is saturated (i.e.,containing single C—C bonds only) or unsaturated (i.e., containing oneor more double bonds or triple bonds). A fully saturated carbocyclylradical is also referred to as “cycloalkyl.” Examples of monocycliccycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl isalso referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenylsinclude, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Polycyclic carbocyclyl radicals include, for example,adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unlessotherwise stated specifically in the specification, the term“carbocyclyl” is meant to include carbocyclyl radicals that areoptionally substituted by one or more substituents independentlyselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^(c)-carbocyclylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkynyl” refers to a radical of the formula—R^(c)-carbocyclyl where R^(c) is an alkynylene chain as defined above.The alkynylene chain and the carbocyclyl radical is optionallysubstituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-carbocyclyl where R^(c) is an alkylene chain asdefined above. The alkylene chain and the carbocyclyl radical isoptionally substituted as defined above.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical, biological and/orchemical properties as a carboxylic acid moiety. Examples of carboxylicacid bioisosteres include, but are not limited to,

and the like.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Insome embodiments, the alkyl part of the fluoroalkyl radical isoptionally substituted as defined above for an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises two to twelve carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radical isa monocyclic, bicyclic, tricyclic or tetracyclic ring system, whichoptionally includes fused or bridged ring systems. The heteroatoms inthe heterocyclyl radical are optionally oxidized. One or more nitrogenatoms, if present, are optionally quaternized. The heterocyclyl radicalis partially or fully saturated. The heterocyclyl is attached to therest of the molecule through any atom of the ring(s). Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen and where thepoint of attachment of the heterocyclyl radical to the rest of themolecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include,but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include,but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl,2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula—R^(c)-heterocyclyl where R^(c) is an alkylene chain as defined above.If the heterocyclyl is a nitrogen-containing heterocyclyl, theheterocyclyl is optionally attached to the alkyl radical at the nitrogenatom. The alkylene chain of the heterocyclylalkyl radical is optionallysubstituted as defined above for an alkylene chain. The heterocyclylpart of the heterocyclylalkyl radical is optionally substituted asdefined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atomof the formula —O—R^(c)-heterocyclyl where R^(c) is an alkylene chain asdefined above. If the heterocyclyl is a nitrogen-containingheterocyclyl, the heterocyclyl is optionally attached to the alkylradical at the nitrogen atom. The alkylene chain of theheterocyclylalkoxy radical is optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkoxyradical is optionally substituted as defined above for a heterocyclylgroup.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical is a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

The compounds disclosed herein, in some embodiments, contain one or moreasymmetric centers and thus give rise to enantiomers, diastereomers, andother stereoisomeric forms that are defined, in terms of absolutestereochemistry, as (R)- or (S)-. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans.) Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein, in certain embodiments, exist as tautomers.In circumstances where tautomerization is possible, a chemicalequilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

The compounds disclosed herein, in some embodiments, are used indifferent enriched isotopic forms, e.g., enriched in the content of ²H,³H, ¹¹C, ¹³C and/or ¹⁴C. In one particular embodiment, the compound isdeuterated in at least one position. Such deuterated forms can be madeby the procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997. Asdescribed in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration canimprove the metabolic stability and or efficacy, thus increasing theduration of action of drugs.

Unless otherwise stated, structures depicted herein are intended toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of the present disclosure.

The compounds of the present disclosure optionally contain unnaturalproportions of atomic isotopes at one or more atoms that constitute suchcompounds. For example, the compounds may be labeled with isotopes, suchas for example, deuterium (2H), tritium (3H), iodine-125 (¹²⁵I) orcarbon-14 (¹⁴C). Isotopic substitution with ²H, ¹¹C, ¹³C, ¹⁴C, ¹⁵C, ¹²N,¹³N, ¹⁵N, ¹⁶N, ¹⁶O, ¹⁷O, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F, ³³S, ³⁴S, ³⁵S, ³⁶S,³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, ¹²⁵I are all contemplated. In some embodiments,isotopic substitution with ¹⁸F is contemplated. All isotopic variationsof the compounds of the present invention, whether radioactive or not,are encompassed within the scope of the present invention.

In certain embodiments, the compounds disclosed herein have some or allof the ¹H atoms replaced with ²H atoms. The methods of synthesis fordeuterium-containing compounds are known in the art and include, by wayof non-limiting example only, the following synthetic methods.

Deuterium substituted compounds are synthesized using various methodssuch as described in: Dean, Dennis C.; Editor. Recent Advances in theSynthesis and Applications of Radiolabeled Compounds for Drug Discoveryand Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; GeorgeW.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds viaOrganometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; andEvans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal.Chem., 1981, 64(1-2), 9-32.

Deuterated starting materials are readily available and are subjected tothe synthetic methods described herein to provide for the synthesis ofdeuterium-containing compounds. Large numbers of deuterium-containingreagents and building blocks are available commercially from chemicalvendors, such as Aldrich Chemical Co.

Deuterium-transfer reagents suitable for use in nucleophilicsubstitution reactions, such as iodomethane-d₃ (CD₃I), are readilyavailable and may be employed to transfer a deuterium-substituted carbonatom under nucleophilic substitution reaction conditions to the reactionsubstrate. The use of CD₃I is illustrated, by way of example only, inthe reaction schemes below.

Deuterium-transfer reagents, such as lithium aluminum deuteride(LiAlD₄), are employed to transfer deuterium under reducing conditionsto the reaction substrate. The use of LiAlD₄ is illustrated, by way ofexample only, in the reaction schemes below.

Deuterium gas and palladium catalyst are employed to reduce unsaturatedcarbon-carbon linkages and to perform a reductive substitution of arylcarbon-halogen bonds as illustrated, by way of example only, in thereaction schemes below.

In one embodiment, the compounds disclosed herein contain one deuteriumatom. In another embodiment, the compounds disclosed herein contain twodeuterium atoms. In another embodiment, the compounds disclosed hereincontain three deuterium atoms. In another embodiment, the compoundsdisclosed herein contain four deuterium atoms. In another embodiment,the compounds disclosed herein contain five deuterium atoms. In anotherembodiment, the compounds disclosed herein contain six deuterium atoms.In another embodiment, the compounds disclosed herein contain more thansix deuterium atoms. In another embodiment, the compound disclosedherein is fully substituted with deuterium atoms and contains nonon-exchangeable ¹H hydrogen atoms. In one embodiment, the level ofdeuterium incorporation is determined by synthetic methods in which adeuterated synthetic building block is used as a starting material.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of theheteroaromatic RAF inhibitory compounds described herein is intended toencompass any and all pharmaceutically suitable salt forms. Preferredpharmaceutically acceptable salts of the compounds described herein arepharmaceutically acceptable acid addition salts and pharmaceuticallyacceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and. aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basiccompounds are, in some embodiments, prepared by contacting the free baseforms with a sufficient amount of the desired acid to produce the saltaccording to methods and techniques with which a skilled artisan isfamiliar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts are, insome embodiments, formed with metals or amines, such as alkali andalkaline earth metals or organic amines. Salts derived from inorganicbases include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts and the like. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, for example,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine,hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline,N-methylglucamine, glucosamine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. See Berge et al., supra.

“Pharmaceutically acceptable solvate” refers to a composition of matterthat is the solvent addition form. In some embodiments, solvates containeither stoichiometric or non-stoichiometric amounts of a solvent, andare formed during the process of making with pharmaceutically acceptablesolvents such as water, ethanol, and the like. Hydrates are formed whenthe solvent is water, or alcoholates are formed when the solvent isalcohol. Solvates of compounds described herein are convenientlyprepared or formed during the processes described herein. The compoundsprovided herein optionally exist in either unsolvated as well assolvated forms. The term “subject” or “patient” encompasses mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. In one aspect, the mammal is a human.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably. These terms refer to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient is still afflicted with the underlying disorder. Forprophylactic benefit, the compositions are, in some embodiments,administered to a patient at risk of developing a particular disease, orto a patient reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease has not been made.

The RAF Family of Kinases

The RAF kinases are a family of serine/thronine protein kinasesconstitute core components of the RAS-RAF-MEK-ERK mitogen activatedprotein kinase (MAPK) signalling cascade (also known as the MAPK/ERKpathway), a pathway that mediates signals from cell surface receptors tothe nucleus to regulate cell growth, differentiation and survival. TheRAF proteins are related to retroviral oncogenes and are structurallyconserved from metazoans to mammals, as is the MAPK/ERK pathway. Theirdysregulation leads to uncontrolled cellular proliferation, survival anddedifferentiation. Consequently, RAF kinases are altered orinappropriately activated in a majority of cancers.

The MAPK/ERK signalling pathway is a network of proteins in the cellthat communicates a signal from a receptor on the surface of the cell tothe DNA in the nucleus of the cell. The signal starts when a signalingmolecule binds to the receptor on the cell surface and ends when the DNAin the nucleus expresses a protein and produces some change in the cell,such as cell division. The pathway includes many proteins, whichcommunicate by adding phosphate groups to a neighboring protein, whichacts as a molecular “on” or “off” switch, and overall the pathway can bedivided into 3 steps: (i) Ras activation, (ii) a kinase signaltransduction cascade, and (iii) regulation of translation andtranscription. Briefly, an extracellular mitogen or a signaling moleculebinds to the membrane receptor. This allows Ras (a small GTPase) to swapits GDP for a GTP and become active. Activated Ras activates the proteinkinase activity of RAF kinase. RAF kinase phosphorylates and activatesMEK (MEK1 and MEK2). MEK then phosphorylates and activates a MAPK (alsoknown as ERK). MAPK activation regulates activities of severaltranscription factors and also alters the translation of mRNA toproteins. By altering the levels and activities of transcriptionfactors, MAPK leads to altered transcription of genes that are importantfor the cell cycle.

There are three known mammalian RAF isoforms: C-RAF (also known asRAF-1, or c-RAF-1), B-RAF, and A-RAF. All RAF kinases share a commonmodular structure consisting of 3 conserved regions (CR1, CR2, and CR3)with distinct functions. CR1 contains (i) a Ras-binding domain (RBD),which is necessary for the interaction with Ras and with membranephospholipids required for membrane recruitment, and (ii) acysteine-rich domain (CRD), which is a secondary Ras-binding site andalso necessary for the interaction of CR1 with the kinase domain for RAFautoinhibition. CR2 contains important inhibitory phosphorylation sitesparticipating in the negative regulation of Ras binding and RAFactivation. CR3 features the kinase domain, including the activationsegment, whose phosphorylation is crucial for kinase activation.

Functionally, the RAF structure can be split into a regulatoryN-terminal region, containing the RBD, which is critical for activationas well as inhibitory phosphorylation sites, and a catalytic C-terminalregion, which includes phosphorylation sites necessary for the kinaseactivation. The regulatory domain restrains the activity of the kinasedomain, and its removal results in constitutive oncogenic activation.However, the activity of the isolated C-RAF kinase domain is subjectedto further regulation and can be stimulated by phorbol esters, v-Src,and phosphorylation.

The common and key step in the activation of all 3 RAF kinase isoformsis membrane recruitment by a Ras family protein. The RAF kinases arelocated in the cytosol in their inactive state when bound to 14-3-3proteins. In the presence of active Ras, they translocate to the plasmamembrane. Membrane translocation triggers further activation events,such as the binding of PP2A to dephosphorylate the inhibitory pS259 sitein RAF-1 (and presumably the corresponding sites in A-RAF and B-RAF) andthe co-localization with the kinases responsible for the multipleactivating phosphorylations. The sequences forming the binding interfaceare well conserved in the RAF as well as Ras family indicating thatseveral members of the Ras family have the ability to bind RAF kinases.H-Ras, N-Ras, and K-Ras stimulate all 3 RAF isoforms and are the onlyRas proteins that activate B-RAF. In contrast, A-RAF is also activatedby R-Ras3, while C-RAF responds weakly to R-Ras3, Rit, and TC21 as well.But, all RAF kinases share MEK1/2 kinases as substrates. MEK1/2 in turnactivate ERK1/2, and this pathway regulates many cellular functions suchas cell proliferation, differentiation, migration, or apoptosis.

C-RAF

C-RAF was first to be identified and is a ubiquitously expressedisoform. In humans, C-RAF is encoded by the RAF1 gene. C-RAF also has aknown splice variant preferentially expressed in the muscle and brain.C-RAF plays a critical role in mediating the cellular effects of growthfactor signals. In the inactive state, C-RAF exists in a closedconformation in which the N-terminal regulatory region folds over andoccludes the catalytic region. This conformation is stabilized by a14-3-3 dimer binding to an N-terminal site, phospho-S259 (pS259), and aC-terminal site, pS621. Dephosphorylation of pS259 at the cell membraneby specific phosphatases (PP2A, PP1) releases 14-3-3 from its N-terminalbinding site in C-RAF, thereby allowing conformational changes to occurthat unmask the RBD and CRD domains in the CR1 region to enable Rasbinding and membrane recruitment.

B-RAF

B-RAF is encoded in humans by the BRAF gene, also known asproto-oncogene B-RAF and v-RAF murine sarcoma viral oncogene homolog B.Alternative splicing gives rise to multiple B-RAF isoforms which aredifferentially expressed in various tissues. Whereas activation of A-RAFand C-RAF requires both phosphorylation and dephosphorylation of certainresidues, as well as binding to other proteins, B-RAF becomes activatedimmediately upon translocation to the plasma membrane. B-RAF exhibitshigher basal kinase activity than A-RAF and C-RAF. B-RAF requires Rasand 14-3-3 binding for its activation and is inhibited or activated byPKA depending on the levels of 14-3-3 expression, which need to be highfor permitting activation. B-RAF activity is also regulated by splicing.B-RAF isoforms containing exon 8b are more phosphorylated on theinhibitory S365 site, leading to an increased interaction with 14-3-3and strengthening the inhibitory interaction between N-terminalregulatory domain and kinase domain, altogether resulting in lowerkinase activity.

A-RAF

Serine/threonine-protein kinase A-RAF or A-RAF is an enzyme encoded bythe ARAF gene in humans. There are 2 known splice isoforms ofA-RAF-DA-RAF1 and D-RAF2. They lack the kinase domain and act asdominant inhibitory mutants of Ras and ARF GTPases. DA-RAF1 is apositive regulator of myogenic differentiation by mediating theinhibition of the ERK pathway required for differentiation. There areseveral ways A-RAF is different from the other RAF kinases. A-RAF is theonly steroid hormone-regulated Raf isoform. In addition, theA-RAFprotein has amino acid substitutions in a negatively charged regionupstream of the kinase domain (N-region), which contributes to its lowbasal activity. A-RAF is also only weakly activated by oncogenic H-Rasand Src and also displays low kinase activity towards MEK (the lowestkinase activity towards MEK proteins in the Raf kinase family). Inaddition to phosphorylating MEK, A-RAF also inhibits MST2, a tumorsuppressor and pro-apoptotic kinase not found in the MAPK pathway. Byinhibiting MST2, A-RAF prevents apoptosis from occurring. However, thisinhibition is only occurs when the splice factor heterogenous nuclearribonucleoprotein H (hnRNP H) maintains the expression of a full-lengthA-RAF protein. Tumorous cells often overexpress hnRNP H which leads tofull-length expression of A-Raf which then inhibits apoptosis, allowingcancerous cells that should be destroyed to stay alive. A-RAF also bindsto pyruvate kinase M2 (PKM2), again outside the MAPK pathway. PKM2 is anisozyme of pyruvate kinase that is responsible for the Warburg effect incancer cells. A-RAF upregulates the activity of PKM2 by promoting aconformational change in PKM2. This causes PKM2 to transition from itslow-activity dimeric form to a highly active tetrameric form. Thiscauses more glucose carbons to be converted to pyruvate and lactate,producing energy for the cell, linking A-Raf to energy metabolismregulation and cell transformation, both of which are very important intumorigenesis.

RAF Kinase Inhibitors

Aberrant activation of the MAPK/ERK pathway is frequently found invarious cancers and is a target for cancer therapeutics. In particular,B-RAF has emerged as one of the most attractive molecular targets forcancer therapeutics because somatic mutations of B-RAF have frequentlybeen found in human tumors. Approximately 20% of all cancer samplestested to date harbor mutations in B-RAF. B-RAF-V600E, a missensemutation in the kinase domain generated by the substitution of glutamicacid with valine at position 600 is the most common B-RAF mutation.C-RAF is mutated in ˜1% of the various tumor types tested and the rateof mutations in A-RAF is even lower. B-RAF and C-RAF form both homo- andheterodimers as part of their activation mechanism and A-RAF stabilizesthe B-RAF:C-RAF complexes to sustain signaling efficiency. Also, it isC-RAF, not B-RAF, that transmits signals from oncogenic RAS to MEK.Therefore, in different contexts, each of the RAF isoforms act as apotential therapeutic target.

Sorafenib was the first RAF inhibitor to enter clinical trials.Sorafenib is a broad specificity drug that inhibits additional kinases,including vascular endothelial growth factor receptor family (VEGFR-2and VEGFR-3), platelet-derived growth factor receptor family (PDGFR-band KIT) and FLT3. Clinical trials showed no correlation between theclinical responses with B-RAF mutation status, indicating it is a poorinhibitor of B-RAF. This led to the development of a new generation ofB-RAF inhibitors, including, but not limited to vemurafenib, SB-590885,and dabrafenib (GSK2118436). Although the initial results of theclinical studies in B-RAF-mutant melanoma were encouraging, as clinicaltesting began in other B-RAF-mutated cancers (such as thyroid andcolorectal cancers) it became apparent that tumors of different celltypes harboring B-RAF mutations responded differently to selective B-RAFinhibition. Moreover, the existence of both primary and secondaryresistance to RAF inhibition poses as one of the greatest challenge tothe progress of RAF kinase inhibitor therapy. The mechanisms ofresistance fall into two broad categories. Intrinsic/primary resistanceis displayed by approximately 50% of patients. The other 50% of thepatients initially respond (>30% tumor shrinkage) to RAF inhibitor butsubsequently develop progressive disease associated withacquired/secondary resistance to RAF inhibitor. These two categories arenot mutually exclusive because nearly all responders have remainingdisease and, thus, may display intrinsic resistance. The determinants ofprimary RAF inhibitor resistance seem to vary with tumor type, withalteration in RTK signaling also being involved. Potential mechanisms ofsecondary B-RAF inhibitor resistance include, but are not limited to,reactivation of ERK1/2 pathways, upregulation of RTK signaling, theupregulation of receptor tyrosine kinases, mutations in RAS, andupregulation of COT. B-Raf alternative splicing and amplification ofB-RAF-V600E have also been implicated in ˜30 and 20% of patients,respectively. Moreover, RAF kinase inhibitors cause paradoxicalactivation of the MAPK pathway, which, in some instances, leads to thedevelopment of secondary RAS mutation-driven malignancies. As such,there is a need in the field for new RAF kinase inhibitors that overcomethe existing pitfalls and challenges posed by the current inhibitors.

Heteroaromatic RAF Inhibitory Compounds

In one aspect, provided herein is a heteroaromatic RAF inhibitorycompound.

One embodiment provides a compound, or pharmaceutically acceptable saltor solvate thereof, having the structure of Formula (I):

wherein,

-   -   X is N or C—H;    -   R¹ is selected from H, optionally substituted C1-C6 alkyl, or        optionally substituted C3-C7 cycloalkyl;    -   R² is selected from H, optionally substituted C1-C6 alkyl, or        optionally substituted C3-C7 cycloalkyl; or optionally, R¹ and        R² join to form a ring;    -   R³ is selected from H, —OH, —OR⁴, —NH₂, —NHR⁴, —N(R⁴)₂,        optionally substituted heterocyclyl, or optionally substituted        heteroaryl;    -   each R⁴ is independently selected from optionally substituted        C1-C6 alkyl, optionally substituted C1-C6 acyl or optionally, R²        and R⁴ join to form a ring; and    -   Z is an optionally substituted aryl or heteroaryl.

One embodiment provides the compound of Formula (I), or pharmaceuticallyacceptable salt or solvate thereof, wherein X is N.

One embodiment provides the compound of Formula (I), or pharmaceuticallyacceptable salt or solvate thereof, wherein X is C—H.

One embodiment provides the compound of Formula (I), or pharmaceuticallyacceptable salt or solvate thereof, wherein R¹ is H. Another embodimentprovides the compound, or pharmaceutically acceptable salt or solvatethereof, wherein R¹ is optionally substituted C1-C6 alkyl. Anotherembodiment provides the compound, or pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted alkyl is substitutedwith at least one halogen. Another embodiment provides the compound, orpharmaceutically acceptable salt or solvate thereof, wherein R¹ is CH₃.Another embodiment provides the compound, or pharmaceutically acceptablesalt or solvate thereof, wherein R¹ is CF₃. Another embodiment providesthe compound, or pharmaceutically acceptable salt or solvate thereof,wherein R¹ is optionally substituted C3-C7 cycloalkyl.

One embodiment provides the compound of Formula (I), or pharmaceuticallyacceptable salt or solvate thereof, wherein R² is H. Another embodimentprovides the compound, or pharmaceutically acceptable salt or solvatethereof, wherein R² is optionally substituted C1-C6 alkyl. Anotherembodiment provides the compound, or pharmaceutically acceptable salt orsolvate thereof, wherein R² is optionally substituted C3-C7 cycloalkyl.

One embodiment provides the compound of Formula (I), or pharmaceuticallyacceptable salt or solvate thereof, wherein R¹ and R² join to form aring. Another embodiment provides the compound, or pharmaceuticallyacceptable salt or solvate thereof, wherein R¹ and R² join to form anoptionally substituted cycloalkyl ring. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein R¹ and R² join to form an optionally substituted heterocyclylring. Another embodiment provides the compound, or pharmaceuticallyacceptable salt or solvate thereof, wherein the optionally substitutedheterocyclyl ring is selected from an optionally substitutedpyrrolidine, optionally substituted piperidine, optionally substitutedazetidine, optionally substituted tetrahydropyran, optionallysubstituted tetrahydrofuran or optionally substituted oxetane.

One embodiment provides the compound of Formula (I), or pharmaceuticallyacceptable salt or solvate thereof, wherein R¹ and R² are bothoptionally substituted C1-C6 alkyl. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein R¹ and R² are CH₃.

One embodiment provides the compound of Formula (I), or pharmaceuticallyacceptable salt or solvate thereof, wherein R³ is —OH. Anotherembodiment provides the compound, or pharmaceutically acceptable salt orsolvate thereof, wherein R³ is —NH₂. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein R³ is —NHR⁴. Another embodiment provides the compound, orpharmaceutically acceptable salt or solvate thereof, wherein R³ is—N(R⁴)₂. Another embodiment provides the compound, or pharmaceuticallyacceptable salt or solvate thereof, wherein R³ is —OR⁴. Anotherembodiment provides the compound, or pharmaceutically acceptable salt orsolvate thereof, wherein R³ is optionally substituted heterocyclyl.Another embodiment provides the compound, or pharmaceutically acceptablesalt or solvate thereof, wherein R³ is optionally substitutedheteroaryl.

One embodiment provides the compound of Formula (I), or pharmaceuticallyacceptable salt or solvate thereof, wherein R⁴ is optionally substitutedC1-C6 alkyl. Another embodiment provides the compound, orpharmaceutically acceptable salt or solvate thereof, wherein R⁴ isoptionally substituted C1-C6 acyl.

One embodiment provides the compound of Formula (I), or pharmaceuticallyacceptable salt or solvate thereof, wherein R² and R⁴ join to form aring. Another embodiment provides the compound, or pharmaceuticallyacceptable salt or solvate thereof, wherein R² and R⁴ join to form anoptionally substituted heterocyclyl ring. Another embodiment providesthe compound, or pharmaceutically acceptable salt or solvate thereof,wherein optionally substituted heterocyclyl ring is an oxopyrrolidinering, or an optionally substituted oxomorpholine ring.

One embodiment provides the compound of Formula (I), or pharmaceuticallyacceptable salt or solvate thereof, wherein Z is an optionallysubstituted aryl. Another embodiment provides the compound, orpharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted aryl is an optionally substituted phenyl. Anotherembodiment provides the compound, or pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted phenyl is anoptionally substituted 3-(trifluoromethyl)phenyl. Another embodimentprovides the compound, or pharmaceutically acceptable salt or solvatethereof, wherein Z is a 3-(trifluoromethyl)phenyl.

One embodiment provides the compound of Formula (I), or pharmaceuticallyacceptable salt or solvate thereof, wherein Z is an optionallysubstituted heteroaryl. Another embodiment provides the compound, orpharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted heteroaryl is an optionally substitutedsix-membered heteroaryl. Another embodiment provides the compound, orpharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted six-membered heteroaryl is an optionallysubstituted pyridyl. Another embodiment provides the compound, orpharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted six-membered heteroaryl is an optionallysubstituted pyrimidine. Another embodiment provides the compound, orpharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted pyridyl is an optionally substituted2-(trifluoromethyl)pyrid-4-yl. Another embodiment provides the compound,or pharmaceutically acceptable salt or solvate thereof, wherein Z is a2-(trifluoromethyl)pyrid-4-yl.

One embodiment provides a compound, or pharmaceutically acceptable saltor solvate thereof, having the structure of Formula (II):

wherein,

-   -   X is N or C—H;    -   R¹ is selected from H, optionally substituted C1-C6 alkyl, or        optionally substituted C3-C7 cycloalkyl;    -   R² is selected from H, optionally substituted C1-C6 alkyl, or        optionally substituted C3-C7 cycloalkyl; or optionally, R¹ and        R² join to form a ring;    -   R³ is selected from H, —OH, —OR⁴, —NH₂, —NHR⁴, —N(R⁴)₂,        optionally substituted heterocyclyl, or optionally substituted        heteroaryl;    -   each R⁴ is independently selected from optionally substituted        C1-C6 alkyl, optionally substituted C1-C6 acyl or optionally, R²        and R⁴ join to form a ring; and    -   Z is an optionally substituted aryl or heteroaryl.

One embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt or solvate thereof, wherein X is N.

One embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt or solvate thereof, wherein X is C—H.

One embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt or solvate thereof, wherein R¹ is H.Another embodiment provides the compound, or pharmaceutically acceptablesalt or solvate thereof, wherein R¹ is optionally substituted C1-C6alkyl. Another embodiment provides the compound, or pharmaceuticallyacceptable salt or solvate thereof, wherein the optionally substitutedalkyl is substituted with at least one halogen. Another embodimentprovides the compound, or pharmaceutically acceptable salt or solvatethereof, wherein R¹ is CH₃. Another embodiment provides the compound, orpharmaceutically acceptable salt or solvate thereof, wherein R¹ is CF₃.Another embodiment provides the compound, or pharmaceutically acceptablesalt or solvate thereof, wherein R¹ is optionally substituted C3-C7cycloalkyl.

One embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt or solvate thereof, wherein R² is H.Another embodiment provides the compound, or pharmaceutically acceptablesalt or solvate thereof, wherein R² is optionally substituted C1-C6alkyl. Another embodiment provides the compound, or pharmaceuticallyacceptable salt or solvate thereof, wherein R² is optionally substitutedC3-C7 cycloalkyl.

One embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt or solvate thereof, wherein R¹ and R²join to form a ring. Another embodiment provides the compound, orpharmaceutically acceptable salt or solvate thereof, wherein R¹ and R²join to form an optionally substituted cycloalkyl ring. Anotherembodiment provides the compound, or pharmaceutically acceptable salt orsolvate thereof, wherein R¹ and R² join to form an optionallysubstituted heterocyclyl ring. Another embodiment provides the compound,or pharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted heterocyclyl ring is selected from an optionallysubstituted pyrrolidine, optionally substituted piperidine, optionallysubstituted azetidine, optionally substituted tetrahydropyran,optionally substituted tetrahydrofuran or optionally substitutedoxetane.

One embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt or solvate thereof, wherein R¹ and R²are both optionally substituted C1-C6 alkyl. Another embodiment providesthe compound, or pharmaceutically acceptable salt or solvate thereof,wherein R¹ and R² are CH₃.

One embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt or solvate thereof, wherein R³ is —OH.Another embodiment provides the compound, or pharmaceutically acceptablesalt or solvate thereof, wherein R³ is —NH₂. Another embodiment providesthe compound, or pharmaceutically acceptable salt or solvate thereof,wherein R³ is —NHR⁴. Another embodiment provides the compound, orpharmaceutically acceptable salt or solvate thereof, wherein R³ is—N(R⁴)₂. Another embodiment provides the compound, or pharmaceuticallyacceptable salt or solvate thereof, wherein R³ is —OR⁴. Anotherembodiment provides the compound, or pharmaceutically acceptable salt orsolvate thereof, wherein R³ is optionally substituted heterocyclyl.Another embodiment provides the compound, or pharmaceutically acceptablesalt or solvate thereof, wherein R³ is optionally substitutedheteroaryl.

One embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt or solvate thereof, wherein R⁴ isoptionally substituted C1-C6 alkyl. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein R⁴ is optionally substituted C1-C6 acyl.

One embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt or solvate thereof, wherein R² and R⁴join to form a ring. Another embodiment provides the compound, orpharmaceutically acceptable salt or solvate thereof, wherein R² and R⁴join to form an optionally substituted heterocyclyl ring. Anotherembodiment provides the compound, or pharmaceutically acceptable salt orsolvate thereof, wherein optionally substituted heterocyclyl ring is anoxopyrrolidine ring, or an optionally substituted oxomorpholine ring.

One embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt or solvate thereof, wherein Z is anoptionally substituted aryl. Another embodiment provides the compound,or pharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted aryl is an optionally substituted phenyl. Anotherembodiment provides the compound, or pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted phenyl is anoptionally substituted 3-(trifluoromethyl)phenyl. Another embodimentprovides the compound, or pharmaceutically acceptable salt or solvatethereof, wherein Z is a 3-(trifluoromethyl)phenyl.

One embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt or solvate thereof, wherein Z is anoptionally substituted heteroaryl. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein the optionally substituted heteroaryl is an optionallysubstituted six-membered heteroaryl. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein the optionally substituted six-membered heteroaryl is anoptionally substituted pyridyl. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein the optionally substituted six-membered heteroaryl is anoptionally substituted pyrimidine. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein the optionally substituted pyridyl is an optionally substituted2-(trifluoromethyl)pyrid-4-yl. Another embodiment provides the compound,or pharmaceutically acceptable salt or solvate thereof, wherein Z is a2-(trifluoromethyl)pyrid-4-yl.

One embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt or solvate thereof, wherein Z is anoptionally substituted heteroaryl and R¹ and R² are both optionallysubstituted C1-C6 alkyl. Another embodiment provides the compound, orpharmaceutically acceptable salt or solvate thereof, wherein Z is anoptionally substituted pyridyl and R¹ and R² are both optionallysubstituted C1-C6 alkyl. Another embodiment provides the compound, orpharmaceutically acceptable salt or solvate thereof, wherein Z is anoptionally substituted 2-(trifluoromethyl)pyrid-4-yl, and R¹ and R² areboth optionally substituted C1-C6 alkyl. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein Z is a 2-(trifluoromethyl)pyrid-4-yl and R¹ and R² are bothoptionally substituted C1-C6 alkyl. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein Z is a 2-(trifluoromethyl)pyrid-4-yl and R¹ and R² are both CH₃.

One embodiment provides a compound, or pharmaceutically acceptable saltor solvate thereof, having the structure of Formula (III):

wherein,

-   -   X is N or C—H; and    -   Z is an optionally substituted aryl or heteroaryl.

One embodiment provides the compound of Formula (III), orpharmaceutically acceptable salt or solvate thereof, wherein X is N.

One embodiment provides the compound of Formula (III), orpharmaceutically acceptable salt or solvate thereof, wherein X is C—H.

One embodiment provides the compound of Formula (III), orpharmaceutically acceptable salt or solvate thereof, wherein Z is anoptionally substituted aryl. Another embodiment provides the compound,or pharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted aryl is an optionally substituted phenyl. Anotherembodiment provides the compound, or pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted phenyl is anoptionally substituted 3-(trifluoromethyl)phenyl. Another embodimentprovides the compound, or pharmaceutically acceptable salt or solvatethereof, wherein Z is a 3-(trifluoromethyl)phenyl.

One embodiment provides the compound of Formula (III), orpharmaceutically acceptable salt or solvate thereof, wherein Z is anoptionally substituted heteroaryl. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein the optionally substituted heteroaryl is an optionallysubstituted six-membered heteroaryl. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein the optionally substituted six-membered heteroaryl is anoptionally substituted pyridyl. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein the optionally substituted six-membered heteroaryl is anoptionally substituted pyrimidine. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein the optionally substituted pyridyl is an optionally substituted2-(trifluoromethyl)pyrid-4-yl. Another embodiment provides the compound,or pharmaceutically acceptable salt or solvate thereof, wherein Z is a2-(trifluoromethyl)pyrid-4-yl.

One embodiment provides a compound, or pharmaceutically acceptable saltor solvate thereof, having the structure of Formula (IV):

wherein,

-   -   X is N or C—H; and    -   Z is an optionally substituted aryl or heteroaryl.

One embodiment provides the compound of Formula (IV), orpharmaceutically acceptable salt or solvate thereof, wherein X is N.

One embodiment provides the compound of Formula (IV), orpharmaceutically acceptable salt or solvate thereof, wherein X is C—H.

One embodiment provides the compound of Formula (IV), orpharmaceutically acceptable salt or solvate thereof, wherein Z is anoptionally substituted aryl. Another embodiment provides the compound,or pharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted aryl is an optionally substituted phenyl. Anotherembodiment provides the compound, or pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted phenyl is anoptionally substituted 3-(trifluoromethyl)phenyl. Another embodimentprovides the compound, or pharmaceutically acceptable salt or solvatethereof, wherein Z is a 3-(trifluoromethyl)phenyl.

One embodiment provides the compound of Formula (IV), orpharmaceutically acceptable salt or solvate thereof, wherein Z is anoptionally substituted heteroaryl. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein the optionally substituted heteroaryl is an optionallysubstituted six-membered heteroaryl. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein the optionally substituted six-membered heteroaryl is anoptionally substituted pyridyl. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein the optionally substituted six-membered heteroaryl is anoptionally substituted pyrimidine. Another embodiment provides thecompound, or pharmaceutically acceptable salt or solvate thereof,wherein the optionally substituted pyridyl is an optionally substituted2-(trifluoromethyl)pyrid-4-yl. Another embodiment provides the compound,or pharmaceutically acceptable salt or solvate thereof, wherein Z is a2-(trifluoromethyl)pyrid-4-yl.

In some embodiments, the heteroaromatic RAF kinase inhibitory compoundas described herein has a structure provided in Table 1.

TABLE 1 Synthetic Chemistry Example Compound Structure Compound Name  1

N-(3-[2-[(3R)-3-hydroxybut-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl]-4- methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide  2

N-(3-[2-[(3S)-3-hydroxybut-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl]-4- methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide  3

N-[3-[2-(3-hydroxy-3-methylbut-1-yn-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4- methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide  4

N-[3-[2-(3-hydroxyprop-1- yn-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-2- (trifluoromethyl)pyridine- 4-carboxamide  5

(3S)-N-[3-[2-(2-aminopyrimidin-4- yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2- trifluoroethyl)pyrrolidine- 1-carboxamide  6

N-(3-{2-[(3S)-3- aminobut-1-yn-1-yl]-6- (morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-2- (trifluoromethyl)pyridine-4-carboxamide  7

N-(3-{2-[(3R)-3-aminobut- 1-yn-1-yl]-6-(morpholin-4- yl)pyridin-4-yl}-4-methylphenyl)-2- (trifluoromethyl)pyridine- 4-carboxamide  8

N-(3-{2-[3-(dimethylamino)prop-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}-4- methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide  9

N-{4-methyl-3-[2-(morpholin-4-yl)-6-[3- (pyrrolidin-1-yl)prop-1-yn-1-yl]pyridin-4-yl]phenyl}-2- (trifluoromethyl)pyridine-4-carboxamide 10

N-(4-methyl-3-{2-[3- (methylamino)prop-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4- yl}phenyl)-2-(trifluoromethyl)pyridine-4-carboxamide 11

N-(3-{2-[(3S)-3-aminobut- 1-yn-1-yl]-6-(morpholin-4- yl)pyridin-4-yl}-4-methylphenyl)-2-(trifluoromethyl) pyridine-4-carboxamide 12 and 13

N-(4-methyl-3-{2-[(3R)- 3-(methylamino)but-1- yn-1-yl]-6-(morpholin-4-yl)pyridin- 4-yl} phenyl)-2-(trifluoromethyl)pyridine-4-carboxamide and N-[3-[2-(3-hydroxyprop-1-yn-1-yl)-6-(morpholin-4- yl)pyridin-4-yl]-4- methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide +

14

N-(3-{2-[(3S)-3-aminobut-1-yn-1-yl]-6- (morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-2- (trifluoromethyl)pyridine-4-carboxamide 15 and 16

N-{4-methyl-3-[2-(morpholin-4-yl)-6-[(3S)-4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)pyridin-4-yl]phenyl}-2-(trifluoromethyl) pyridine-4-carboxamide andN-{4-methyl-3-[2-(morpholin-4-yl)-6-[(3R)-4,4,4-trifluoro-3-hydroxybut-1- yn-1-yl]pyridin-4-yl]phenyl}-2-(trifluoromethyl)pyridine-4-carboxamide

17

N-{3-[2-(3-amino-3-methylbut-1-yn-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4- methylphenyl}-2-(trifluoromethyl)pyridine-4-carboxamide 18

N-(3-{2-[(3S)-3-aminobut-1-yn-1-yl]-6- (morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-2- (trifluoromethyl)pyridine-4-carboxamide 19

N-(3-{6-[(3S)-3-aminobut-1-yn-1-yl]-5- (morpholin-4-yl)pyridin-3-yl}-4-methylphenyl)-2-(trifluoromethyl) pyridine-4-carboxamide 20

N-(3-{6-[(3R)-3-aminobut-1-yn-1-yl]-5- (morpholin-4-yl)pyridin-3-yl}-4-methylphenyl)-2- (trifluoromethyl)pyridine-4-carboxamide 21

N-(3-{6-[(3R)-3-Hydroxybut-l-yn-1-yl]-5-(morpholin-4-yl)pyridin-3-yl}-4- methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide 22

N-(3-{6-[(3S)-3-Hydroxybut-1-yn-1-yl]-5-(morpholin-4-yl)pyridin-3-yl}-4- methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide 23

N-{3-[6-(3-Hydroxy-3-methylbut- l-yn-1-yl)-5-(morpholin-4-yl)pyridin-3-yl]-4- methylphenyl}-2-(trifluoromethyl)pyridine-4-carboxamide 24

N-{3-[6-(2-Cyclopropylethynyl)-5- (morpholin-4-yl)pyridin-3-yl]-4-methylphenyl}-2-(trifluoromethyl) pyridine-4-carboxamide 25

N-{4-Methyl-3-[5- (morpholin-4-yl)-6-(prop-1-yn-1-yl)pyridin-3-yl]phenyl}-2- (trifluoromethyl)pyridine-4-carboxamide26

N-{3-[6-Ethynyl-5-(morpholin-4-yl) pyridin-3-yl]-4-methylphenyl}-2-(trifluoromethyl)pyridine-4-carboxamide 27

6-Tert-butyl-N- {4-methyl-3-[5- (morpholin-4-yl)-6-(prop-1-yn-1-yl)pyridin-3-yl]phenyl}pyrimidine-4- carboxamide 28

N-(4-methyl-3-(5-morpholino-6- ((tetrahydro-2H-pyran-4-yl)ethynyl)pyridin-3-yl)phenyl)-2- (trifluoromethyl)isonicotinamide 29

5-(5-(2-methyl-5-(2- (trifluoromethyl)isonicotinamido)phenyl)-3-morpholinopyridin-2-yl)pent-4-ynoic acid 30

N-(4-methyl-3-(5-morpholino-6- (pyrrolidin-3-ylethynyl)pyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide 31

N-(3-(6-((1-acetylpyrrolidin-3- yl)ethynyl)-5-morpholinopyridin-3-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide 32

N-(4-methyl-3-(6-((1-methylpyrrolidin-3-yl)ethynyl)-5-morpholinopyridin-3- yl)phenyl)-2-(trifluoromethyl)isonicotinamide 33

N-(4-methyl-3-(6-((1-(methylsulfonyl) pyrrolidin-3-yl)ethynyl)-5-morpholinopyridin-3-yl) phenyl)-2-(trifluoromethyl)isonicotinamide 34

5-fluoro-2-isopropyl-N-(4-methyl-3- (5-morpholino-6-(prop-1-yn-1-yl)pyridin-3-yl)phenyl)isonicotinamide 35

methyl 5-(5-(2-methyl-5-(2- (trifluoromethyl)isonicotinamido)phenyl)-3-morpholinopyridin-2-yl)pent-4-ynoate 36

N-(3-(6-((1-acetylazetidin-3-yl)ethynyl)- 5-morpholinopyridin-3-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide 37

N-(3-(6-(4-hydroxybut-1-yn-1-yl)- 5-morpholinopyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl) isonicotinamide 38

N-(3-(6-((1-acetylpiperidin-3- yl)ethynyl)-5-morpholinopyridin-3-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide 39

N-(3-(6-[1-acetylpiperidin-4- yl)ethynyl)-5-morpholinopyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl) isonicotinamide 40

N-(3-(6-(azetidin-3-ylethynyl)-5- morpholinopyridin-3-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide 41

N-(4-methyl-3-(6-((1-methylazetidin-3-yl)ethynyl)-5-morpholinopyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide 42

N-(3-(6-(5-hydroxypent-1-yn-1-yl)-5- morpholinopyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl) isonicotinamide 43

N-(4-methyl-3-(6-((1-methylpiperidin-4-yl)ethynyl)-5-morpholinopyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide 44

N-(4-methyl-3-(6-((1- (methylsulfonyl)azetidin-3-yl)ethynyl)-5-morpholinopyridin- 3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide 45

N-(4-methyl-3-(5-morpholino-6- ((tetrahydrofuran-3-yl)ethynyl)pyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide 46

N-(4-methyl-3-(6-((1- (methylsulfonyl)piperidin-3-yl)ethynyl)-5-morpholinopyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide 47

N-(4-methyl-3-(6-((1- (methylsulfonyl)piperidin-4-yl)ethynyl)-5-morpholinopyridin- 3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide 48

N-(3-(6-(3-acetamidoprop-1-yn-1-yl)-5- morpholinopyridin-3-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide 49

N-(4-methyl-3-(5-morpholino-6- (3-(2-oxopyrrolidin-1-yl)prop-1-yn-1-yl)pyridin-3-yl)phenyl)-2- (trifluoromethyl)isonicotinamide 50

N-(4-methyl-3-(5-morpholino-6-(3-(3- oxomorpholino)prop-1-yn-1-yl)pyridin-3-yl)phenyl)-2- (trifluoromethyl)isonicotinamide 51

N-(4-methyl-3-(5-morpholino-6- (piperidin-3-ylethynyl)pyridin-3-yl)phenyl)-2- (trifluoromethyl)isonicotinamide 52

N-(4-methyl-3-(6-((1-methylpiperidin-3-yl)ethynyl)-5-morpholinopyridin-3- yl)phenyl)-2-(trifluoromethyl)isonicotinamide 53

N-(3-(6-(4-hydroxy-4-methylpent-1-yn- 1-yl)-5-morpholinopyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl) isonicotinamide 54

N-(4-methyl-3-(5-morpholino-6- (oxetan-3-ylethynyl)pyridin-3-yl)phenyl)-2- (trifluoromethyl)isonicotinamide 55

N-(4-methyl-3-(6-((4-methyltetrahydro-2H-pyran-4-yl)ethynyl)-5-morpholinopyridin-3-yl)phenyl)-2-(trifluoromethyl) isonicotinamide 56

N-(3-(6-(4-methoxybut-1-yn-1-yl)-5- morpholinopyridin-3-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide 57

N-(3-(6-(5-methoxypent-1-yn-1-yl)-5- morpholinopyridin-3-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide 58

N-(4-methyl-3-(5-morpholino- 6-(piperidin-4-ylethynyl)pyridin-3-yl)phenyl)-2-(trifluoromethyl) isonicotinamide

Preparation of Compounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art,starting from commercially available chemicals and/or from compoundsdescribed in the chemical literature. “Commercially available chemicals”are obtained from standard commercial sources including Acros Organics(Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), AvocadoResearch (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), CrescentChemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.),Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan,Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics(Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), MaybridgeChemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah),Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.),Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCIAmerica (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.),and Wako Chemicals USA, Inc. (Richmond, Va.).

Suitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X,in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

Specific and analogous reactants are optionally identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (contact theAmerican Chemical Society, Washington, D.C. for more details). Chemicalsthat are known but not commercially available in catalogs are optionallyprepared by custom chemical synthesis houses, where many of the standardchemical supply houses (e.g., those listed above) provide customsynthesis services. A reference useful for the preparation and selectionof pharmaceutical salts of the compounds described herein is P. H. Stahl& C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag HelveticaChimica Acta, Zurich, 2002.

Pharmaceutical Compositions

In certain embodiments, the heteroaromatic RAF kinase inhibitorycompound described herein is administered as a pure chemical. In otherembodiments, the heteroaromatic RAF kinase inhibitory compound describedherein is combined with a pharmaceutically suitable or acceptablecarrier (also referred to herein as a pharmaceutically suitable (oracceptable) excipient, physiologically suitable (or acceptable)excipient, or physiologically suitable (or acceptable) carrier) selectedon the basis of a chosen route of administration and standardpharmaceutical practice as described, for example, in Remington: TheScience and Practice of Pharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co.,Easton, Pa. (2005)).

Provided herein is a pharmaceutical composition comprising at least oneheteroaromatic RAF kinase inhibitory compound as described herein, or astereoisomer, pharmaceutically acceptable salt, hydrate, or solvatethereof, together with one or more pharmaceutically acceptable carriers.The carrier(s) (or excipient(s)) is acceptable or suitable if thecarrier is compatible with the other ingredients of the composition andnot deleterious to the recipient (i.e., the subject or the patient) ofthe composition.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of Formula (I),(II), (III), or (IV), or a pharmaceutically acceptable salt or solvatethereof.

One embodiment provides a method of preparing a pharmaceuticalcomposition comprising mixing a compound of Formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier.

In certain embodiments, the heteroaromatic RAF kinase inhibitorycompound as described by Formula (I), (II), (III), or (IV), or apharmaceutically acceptable salt or solvate thereof, is substantiallypure, in that it contains less than about 5%, or less than about 1%, orless than about 0.1%, of other organic small molecules, such asunreacted intermediates or synthesis by-products that are created, forexample, in one or more of the steps of a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills,sachets, or capsules of hard or soft gelatin, methylcellulose or ofanother suitable material easily dissolved in the digestive tract. Insome embodiments, suitable nontoxic solid carriers are used whichinclude, for example, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, talcum, cellulose,glucose, sucrose, magnesium carbonate, and the like. (See, e.g.,Remington: The Science and Practice of Pharmacy (Gennaro, 21^(st) Ed.Mack Pub. Co., Easton, Pa. (2005)).

In some embodiments, the heteroaromatic RAF kinase inhibitory compoundas described by Formula (I), (II), (III), or (IV), or pharmaceuticallyacceptable salt or solvate thereof, is formulated for administration byinjection. In some instances, the injection formulation is an aqueousformulation. In some instances, the injection formulation is anon-aqueous formulation. In some instances, the injection formulation isan oil-based formulation, such as sesame oil, or the like.

The dose of the composition comprising at least one heteroaromatic RAFkinase inhibitory compound as described herein differs depending uponthe subject or patient's (e.g., human) condition. In some embodiments,such factors include general health status, age, and other factors.

Pharmaceutical compositions are administered in a manner appropriate tothe disease to be treated (or prevented). An appropriate dose and asuitable duration and frequency of administration will be determined bysuch factors as the condition of the patient, the type and severity ofthe patient's disease, the particular form of the active ingredient, andthe method of administration. In general, an appropriate dose andtreatment regimen provides the composition(s) in an amount sufficient toprovide therapeutic and/or prophylactic benefit (e.g., an improvedclinical outcome, such as more frequent complete or partial remissions,or longer disease-free and/or overall survival, or a lessening ofsymptom severity. Optimal doses are generally determined usingexperimental models and/or clinical trials. The optimal dose dependsupon the body mass, weight, or blood volume of the patient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one tofour times, or more, per day.

Methods of Treatment

One embodiment provides a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, for use in a method of treatment ofthe human or animal body.

One embodiment provides a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, for use in a method of treatment ofcancer or neoplastic disease.

One embodiment provides a use of a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, in the manufactureof a medicament for the treatment of cancer or neoplastic disease.

In some embodiments, described herein is a method of treating cancer ina patient in need thereof comprising administering to the patient acompound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, described herein is a method oftreating cancer in a patient in need thereof comprising administering tothe patient a pharmaceutical composition comprising a compound ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof,and a pharmaceutically acceptable excipient.

One embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof, for use in a methodof treatment of the human or animal body.

One embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof, for use in a methodof treatment of cancer or neoplastic disease.

One embodiment provides a use of a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof, in the manufactureof a medicament for the treatment of cancer or neoplastic disease.

In some embodiments, described herein is a method of treating cancer ina patient in need thereof comprising administering to the patient acompound of Formula (II), or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, described herein is a method oftreating cancer in a patient in need thereof comprising administering tothe patient a pharmaceutical composition comprising a compound ofFormula (II), or a pharmaceutically acceptable salt or solvate thereof,and a pharmaceutically acceptable excipient.

One embodiment provides a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, for use in a methodof treatment of the human or animal body.

One embodiment provides a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, for use in a methodof treatment of cancer or neoplastic disease.

One embodiment provides a use of a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, in the manufactureof a medicament for the treatment of cancer or neoplastic disease.

In some embodiments, described herein is a method of treating cancer ina patient in need thereof comprising administering to the patient acompound of Formula (III), or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, described herein is a method oftreating cancer in a patient in need thereof comprising administering tothe patient a pharmaceutical composition comprising a compound ofFormula (III), or a pharmaceutically acceptable salt or solvate thereof,and a pharmaceutically acceptable excipient.

One embodiment provides a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof, for use in a methodof treatment of the human or animal body.

One embodiment provides a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof, for use in a methodof treatment of cancer or neoplastic disease.

One embodiment provides a use of a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof, in the manufactureof a medicament for the treatment of cancer or neoplastic disease.

In some embodiments, described herein is a method of treating cancer ina patient in need thereof comprising administering to the patient acompound of Formula (IV), or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, described herein is a method oftreating cancer in a patient in need thereof comprising administering tothe patient a pharmaceutical composition comprising a compound ofFormula (IV), or a pharmaceutically acceptable salt or solvate thereof,and a pharmaceutically acceptable excipient.

Provided herein is the method wherein the pharmaceutical composition isadministered orally. Provided herein is the method wherein thepharmaceutical composition is administered by injection.

Other embodiments and uses will be apparent to one skilled in the art inlight of the present disclosures. The following examples are providedmerely as illustrative of various embodiments and shall not be construedto limit the invention in any way.

EXAMPLES I. Chemical Synthesis

In some embodiments, the heteroaromatic RAF kinase inhibitory compoundsdisclosed herein are synthesized according to the following examples. Asused below, and throughout the description of the invention, thefollowing abbreviations, unless otherwise indicated, shall be understoodto have the following meanings:

-   ° C. degrees Celsius-   δ_(H) chemical shift in parts per million downfield from    tetramethylsilane-   DCM dichloromethane (CH₂Cl₂)-   DMF dimethylformamide-   DMSO dimethylsulfoxide-   EA ethyl acetate-   ESI electrospray ionization-   Et ethyl-   g gram(s)-   h hour(s)-   HPLC high performance liquid chromatography-   Hz hertz-   J coupling constant (in NMR spectrometry)-   LCMS liquid chromatography mass spectrometry-   μ micro-   m multiplet (spectral); meter(s); milli-   M molar-   M⁺ parent molecular ion-   Me methyl-   MHz megahertz-   min minute(s)-   mol mole(s); molecular (as in mol wt)-   mL milliliter-   MS mass spectrometry-   nm nanometer(s)-   NMR nuclear magnetic resonance-   pH potential of hydrogen; a measure of the acidity or basicity of an    aqueous solution-   PE petroleum ether-   RT room temperature-   s singlet (spectral)-   t triplet (spectral)-   T temperature-   TFA trifluoroacetic acid-   THF tetrahydrofuran

Intermediate 1: Tert-butylN-(1-{2-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]ethynyl}cyclopropyl)carbamate

Step 1: 4-(4,6-Dichloropyridin-2-yl)morpholine

To a stirred mixture of 2,4,6-trichloropyridine (29.2 g, 160.061 mmol),morpholine (14 mL, 160.061 mmol) in 1,4-dioxane (160 mL) was added DIEA(28 mL, 160.061 mmol). The reaction mixture was stirred for 16 h at 85°C. under nitrogen atmosphere. The resulting mixture was allowed to cooldown to room temperature. The reaction was quenched with water (700 mL).The resulting mixture was extracted with EtOAc (3×600 mL). The combinedorganic layers was washed with brine (3×400 mL), dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with PE/EA (3/1). The fractions contained desired product werecombined and concentrated to afford4-(4,6-dichloropyridin-2-yl)morpholine (24.77 g, 66%) as a white solid.MS ESI calculated for C₉H₁₀Cl₂N₂O [M+H]⁺, 233.02; found 233.00. ¹H NMR(400 MHz, Chloroform-d) δ 6.68 (d, J=1.6 Hz, 1H), 6.49 (d, J=1.2 Hz,1H), 3.82-3.80 (m, 4H), 3.55-3.52 (m, 4H).

Step 2: Tert-butylN-(1-{2-[4-chloro-6-(morpholin-4-ylpyridin-2-yl]ethynyl}cyclopropyl)carbamate

To a stirred mixture of 4-(4,6-dichloropyridin-2-yl)morpholine (350 mg,1.502 mmol), tert-butyl N-(1-ethynylcyclopropyl)carbamate (353 mg, 1.953mmol), Pd(PPh₃)₂Cl₂ (105 mg, 0.150 mmol) and CuI (57 mg, 0.300 mmol) inDMF (5 mL) was added TEA (1 mL). The reaction mixture was stirred for 4h at 80° C. under nitrogen atmosphere. The resulting mixture wasquenched with water (30 mL). The resulting mixture was extracted withEtOAc (3×25 mL). The combined organic layers was washed with brine (20mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with PE/EtOAc (2/1). The fractionscontained desired product were combined and concentrated to affordtert-butylN-(1-{2-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]ethynyl}cyclopropyl)carbamate(350 mg, 62%) as a light yellow solid. MS ESI calculated forC₁₉H₂₄ClN₃O₃[M+H]⁺, 378.15, 380.15, found 378.05, 380.05. ¹H NMR (400MHz, Chloroform-d) δ 6.78 (s, 1H), 6.54 (d, J=1.6 Hz, 1H), 5.10 (s, 1H),3.83-3.77 (m, 4H), 3.54-3.49 (m, 4H), 1.49 (s, 9H), 1.37-1.34 (m, 2H),1.24-1.20 (m, 2H).

Intermediate 2:(2R)-4-[5-Chloro-3-(morpholin-4-yl)pyridin-2-yl]but-3-yn-2-ol

Step 1: 2,5-Dichloropyridin-3-amine

To a stirred mixture of 2,5-dichloro-3-nitropyridine (5.00 g, 25.909mmol) in EtOH (50 mL) was added SnCl₂.2H₂O (29.00 g, 129.545 mmol) inportions at room temperature. The resulting mixture was stirred for 16 hat 70° C. under nitrogen atmosphere. The resulting mixture wasconcentrated under reduced pressure. The residue was basified to pH 8with saturated Na₂CO₃ (aq.) (200 mL). The resulting mixture wasfiltered, the filter cake was washed with EtOAc (3×50 mL). The combinedfiltrates were extracted with EtOAc (3×100 mL). The combined organiclayers were washed with brine (100 mL), dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, elutedwith PE/EtOAc (4/1). The fractions contained desired product werecombined and concentrated to afford 2,5-dichloropyridin-3-amine (3.00 g,82%) as a light yellow solid. MS ESI calculated for C₅H₄Cl₂N₂[M−H]⁻,160.98, 162.98, 164.98; found 161.20, 163.20, 165.20. ¹H NMR (300 MHz,Chloroform-d) δ 7.76-7.75 (m, 1H), 7.06-7.05 (m, 1H), 4.14 (brs, 2H).

Step 2: 4-(2,5-Dichloropyridin-3-yl)morpholine

To a stirred mixture of 2,5-dichloropyridin-3-amine (3.00 g, 18.405mmol) and NaH (2.00 g, 46.013 mmol, 60%) in DMF (30 mL) was added1-bromo-2-(2-bromoethoxy)ethane (6.00 g, 27.608 mmol). The reactionmixture was stirred for 5 h at room temperature. The reaction wasquenched by the addition of water (100 mL) at room temperature. Theresulting mixture was extracted with EtOAc (3×100 mL). The combinedorganic layers was washed with brine (100 mL), dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with PE/EtOAc (5/1). The fractions contained desired product werecombined and concentrated to afford4-(2,5-dichloropyridin-3-yl)morpholine (3.00 g, 70%) as an orange solid.MS ESI calculated for C₉H₁₀Cl₂N₂O [M+H]⁺, 233.02, 235.02, 237.02; found232.95, 234.95, 236.95. ¹H NMR (400 MHz, Chloroform-d) δ 8.06-8.05 (m,1H), 7.30-7.29 (m, 1H), 3.91-3.80 (m, 4H), 3.12-3.09 (m, 4H).

Step 3: (2R)-4-[5-Chloro-3-(morpholin-4-yl)pyridin-2-yl]but-3-yn-2-ol

To a stirred mixture of 4-(2,5-dichloropyridin-3-yl)morpholine (600 mg,2.574 mmol), (2R)-but-3-yn-2-ol (360 mg, 5.148 mmol), Pd(PPh₃)₂Cl₂ (181mg, 0.257 mmol) and CuI (98 mg, 0.515 mmol) in DMF (6 mL) was added TEA(1 mL). The reaction mixture was degassed with nitrogen for three timesand stirred for 3 h at 80° C. under argon atmosphere. The reactionmixture was allowed to cool down to room temperature. The reaction wasquenched by the addition of water (2 mL) at room temperature. Theresidue was purified by reverse flash chromatography with the followingconditions: column, C18 silica gel; mobile phase, CH₃CN in water (10mmol/L NH₄HCO₃), 15% to 50% gradient in 20 min; detector, UV 254 nm. Thefractions contained desired product were combined and concentrated toafford (2R)-4-[5-chloro-3-(morpholin-4-yl)pyridin-2-yl]but-3-yn-2-ol(500 mg, 73%) as yellow oil. MS ESI calculated for C₁₃H₁₅ClN₂O₂ [M+H]⁺,267.08, 269.08; found 267.05, 269.05. ¹H NMR (400 MHz, DMSO-d₆) δ8.17-8.16 (m, 1H), 7.45-7.49 (m, 1H), 5.57-5.56 (m, 1H), 4.68-4.61 (m,1H), 3.77-3.74 (m, 4H), 3.19-3.17 (m, 4H), 1.39 (d, J=6.6 Hz, 3H).

The following compounds in Table 2 were prepared using proceduressimilar to those described in Intermediate 2 using appropriate startingmaterials.

TABLE 2 Entry Structure IUPAC Name Exact Mass [M + H]⁺ 3

(2S)-4-[5-Chloro- 3-(morpholin-4-yl)- pyridin-2-yl]but-3- yn-2-ol Calc'd267.08, 269.08, found 267.00, 269.00 4

Tert-butyl N-[(2R)- 4-[5-chloro-3- (morpholin-4-yl)- pyridin-2-yl]but-3-yn-2-yl]carbamate Calc'd 366.20, 368.20, found 366.10, 368.10 5

Tert-butyl N-[(2R)- 4-[5-chloro-3- (morpholin-4-yl)- pyridin-2-yl]but-3-yn-2-yl]carbamate Calc'd 366.20, 368.20, found 366.10, 368.10 6

4-[5-Chloro-3- (morpholin-4-yl)- pyridin-2-yl]-2- methylbut-3-yn-2- olCalc'd 281.10, 283.10; found 281.15, 283.15 7

4-[5-Chloro-2-(2- cyclopropylethyn- yl)pyridin-3-yl]- morpholine Calc'd263.09, 265.09; found 263.10, 265.10 8

4-{5-Chloro-2-[2- (trimethylsilyl)- ethynyl]pyridin-3- yl}morpholineCalc'd 295.10, 297.10; found 295.15, 297.15 9

4-[5-Chloro-2- (prop-1-yn-1-yl)- pyridin-3-yl]- morpholine Calc'd237.07, 239.07; found 237.10, 239.10

Intermediate 10:N-(4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide

Step 1:N-(4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide

To a stirred solution of4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.00 g,7.965 mmol) and 2-(trifluoromethyl)pyridine-4-carboxylic acid (1.67 g,8.761 mmol) in CH₃CN (15 mL) were added HATU (4.54 g, 11.947 mmol) andTEA (1.61 g, 15.930 mmol). The resulting mixture was stirred for 16 h atroom temperature. The resulting mixture was diluted with water (50 mL)and extracted with EtOAc (3×50 mL). The combined organic layers waswashed with brine (50 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withPE/EtOAc (1/1). The fractions contained desired product were combinedand concentrated to affordN-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.50 g, 44%) as a yellow solid. MS ESI calculated for C₂₀H₂₂BF₃N₂O₃[M+H]⁺, 407.17, found 407.15. ¹H NMR (400 MHz, Chloroform-d) δ 8.95-8.94(m, 1H), 8.58-8.55 (d, J=8.9 Hz, 1H), 8.16 (s, 1H), 7.98-7.93 (m, 3H),7.02-6.97 (m, 1H), 2.55 (s, 3H), 1.36 (s, 12H).

Example 1:N-(3-[2-[(3R)-3-hydroxybut-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

Preparation 1A:N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide

To a stirred solution of 2-(trifluoromethyl)pyridine-4-carboxylic acid(1.23 g, 6.43 mmol) and HATU (3.26 g, 8.58 mmol) in DMF (10 mL) wereadded TEA (2.38 mL, 23.57 mmol) and4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 g,4.29 mmol). The reaction mixture was stirred for 1.5 h at roomtemperature. The resulting mixture was diluted with water (30 mL) andextracted with EtOAc (3×80 mL). The combined organic layers were washedwith brine (5×40 mL), dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with 25% EtOAc inPE to affordN-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(1.45 g, 83%) as an off-white solid. MS ESI calculated for C₂₀H₂₂BF₃N₂O₃[M+H]⁺, 407.17, found 407.10. ¹H NMR (300 MHz, DMSO-d₆) δ 10.64 (s, 1H),9.00 (d, J=5.0 Hz, 1H), 8.42 (d, J=1.4 Hz, 1H), 8.27-8.19 (m, 1H),8.00-7.88 (m, 2H), 7.23 (d, J=8.2 Hz, 1H), 2.47 (s, 3H), 1.33 (s, 12H).¹⁹F NMR (282 MHz, DMSO-d₆) δ −66.48.

Preparation 1B:N-(3-(2-chloro-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

A mixture of 4-(6-chloro-4-iodopyridin-2-yl)morpholine (2.00 g, 6.162mmol),N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(2.50 g, 6.162 mmol), Na₂CO₃ (1.96 g, 18.486 mmol) andPd(dppf)Cl₂.CH₂Cl₂ (502 mg, 0.616 mmol) in DMF (40 mL) and H₂O (10 mL)was stirred at 60 degrees C. for 2 h under N₂ atmosphere. The reactionwas quenched with water (50 mL) at room temperature. The resultingmixture was extracted with EtOAc (100 mL). The combined organic layerswere washed with brine (3×50 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withPE/EtOAc (1/1) to affordN-(3-(2-chloro-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(2 g, 68%) as a brown solid. MS ESI calculated for C₂₃H₂₀ClF₃N₄O₂[M+H]⁺, 477.12; found 477.20. ¹H NMR (400 MHz, chloroform-d) δ 8.94-8.87(m, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 7.60-7.47 (m, 2H),7.30 (s, 1H), 6.62 (s, 1H), 6.43 (s, 1H), 3.83 (t, J=4.4 Hz, 4H), 3.55(t, J=4.7 Hz, 4H), 2.28 (s, 3H).

Preparation 1:N-(3-[2-[(3R)-3-hydroxybut-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

A mixture of (2R)-but-3-yn-2-ol (88 mg, 1.258 mmol),N-[3-[2-chloro-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(300 mg, 0.629 mmol), XantPhos (36 mg, 0.063 mmol), 2nd GenerationXantPhos precatalyst (56 mg, 0.063 mmol), CuI (6 mg, 0.031 mmol) and TEA(191 mg, 1.887 mmol) in DMF (5 mL) was stirred at 90 degrees C. for 16 hunder N₂ atmosphere. The mixture was allowed to cool down to roomtemperature. The reaction was quenched with water (20 mL). The resultingmixture was extracted with EtOAc (50 mL). The combined organic layerswere washed with brine (3×50 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by Prep-TLC with PE/EtOAc (1/1). The crude waspurified by reverse flash chromatography with the following conditions:Column: C18 Column 120 g; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: CH₃CN; Flow rate: 60 mL/min; Gradient: 30% B to 60% B in30 min; 254/220 nm to affordN-(3-[2-[(3R)-3-hydroxybut-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide(193 mg, 60%) as a light yellow solid. MS ESI calculated forC₂₇H₂₅F3N₄O₃ [M+H]⁺, 511.19 found 511.05. ¹H NMR (400 MHz, chloroform-d)δ 8.94 (d, J=5.0 Hz, 1H), 8.13 (s, 1H), 8.07 (s, 1H), 7.97-7.92 (m, 1H),7.60 (d, J=8.6 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H),6.82 (d, J=1.2 Hz, 1H), 6.54 (d, J=1.2 Hz, 1H), 4.78-4.75 (m, 1H),3.86-3.79 (m, 4H), 3.59-3.51 (m, 4H), 2.29 (s, 3H), 1.57 (d, J=6.7 Hz,3H). ¹⁹F NMR (376 MHz, chloroform-d) δ −67.99 (3F).

Example 2:N-(3-[2-[(3S)-3-hydroxybut-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

Preparation 2:N-(3-[2-[(3S)-3-hydroxybut-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

A mixture ofN-[3-[2-chloro-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(300 mg, 0.629 mmol), (2S)-but-3-yn-2-ol (88 mg, 1.258 mmol), XantPhos(36 mg, 0.063 mmol), DMF (6 mL), 2nd Generation XantPhos precatalyst (56mg, 0.063 mmol), CuI (6 mg, 0.031 mmol) and TEA (191 mg, 1.887 mmol) wasstirred for 16 h at 90 degrees C. under a nitrogen atmosphere. Theresulting mixture was concentrated under reduced pressure. The residuewas purified by reverse phase flash chromatography with the followingconditions: Column: Spherical C18, 20-40 um, 120 g; Mobile Phase A:water (plus 5 mM NH₄HCO₃); Mobile Phase B: CH₃CN; Flow rate: 50 mL/min;Gradient: 5%-5% B, 10 min, 40% B-65% B gradient in 25 min; Detector: 220nm. The fractions containing the desired product were collected at 61% Band concentrated under reduced pressure to affordN-(3-[2-[(3S)-3-hydroxybut-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide(193 mg, 60%) as a white solid. MS ESI calculated for C₂₇H₂₅F₃N₄O₃[M+H]⁺, 511.19, found 511.10. ¹H NMR (400 MHz, chloroform-d) δ 8.91 (d,J=5.0 Hz, 1H), 8.12 (t, J=3.8 Hz, 2H), 7.94-7.92 (m, 1H), 7.59-7.57 (m,1H), 7.49 (d, J=2.4 Hz, 1H), 7.29 (d, J=8.3 Hz, 1H), 6.79 (d, J=1.1 Hz,1H), 6.53 (d, J=1.2 Hz, 1H), 4.75-4.71 (m, 1H), 3.84-3.78 (m, 4H), 3.55(t, J=4.9 Hz, 4H), 2.26 (s, 3H), 1.55 (d, J=6.7 Hz, 3H). ¹⁹F NMR (376MHz, DMSO-d₆) δ −67.98 (3F).

Example 3:N-[3-[2-(3-hydroxy-3-methylbut-1-yn-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide

Preparation 3:N-[3-[2-(3-hydroxy-3-methylbut-1-yn-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide

A mixture ofN-[3-[2-chloro-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(300 mg, 0.629 mmol), 2-methyl-3-butyn-2-ol (106 mg, 1.258 mmol), DMF (3mL), 2nd Generation XantPhos precatalyst (50 mg, 0.063 mmol,), XantPhos(36 mg, 0.063 mmol), CuI (6 mg, 0.031 mmol) and TEA (191 mg, 1.887 mmol)was stirred for 16 h at 60 degrees C. under nitrogen atmosphere. Themixture was allowed to cool down to room temperature. The residue waspurified by reverse phase flash chromatography with the followingconditions: Column: Spherical C18, 20-40 um, 120 g; Mobile Phase A:water (plus 5 mM NH₄HCO₃); Mobile Phase B: CH₃CN; Flow rate: 50 mL/min;Gradient: 5%-5% B, 10 min, 30% B-70% B gradient in 30 min; Detector: 220nm to affordN-[3-[2-(3-hydroxy-3-methylbut-1-yn-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(80 mg, 24%) as a white solid. MS ESI calculated for C₂₈H₂₇F₃N₄O₃[M+H]⁺, 525.20, found 525.10. ¹H NMR (400 MHz, chloroform-d) δ 8.94 (d,J=5.0 Hz, 1H), 8.13 (d, J=5.4 Hz, 2H), 8.00-7.94 (m, 1H), 7.62-7.60 (m,1H), 7.52 (d, J=2.3 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 6.81 (d, J=1.2 Hz,1H), 6.56-6.52 (m, 1H), 3.87-3.80 (m, 4H), 3.58 (t, J=4.9 Hz, 4H), 2.29(s, 3H), 1.64 (s, 6H). ¹⁹F NMR (376 MHz, chloroform-d) δ −67.74 (3F).

Example 4:N-[3-[2-(3-hydroxyprop-1-yn-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide

Preparation 4A: 4-(6-chloro-4-iodopyridin-2-yl)morpholine

A mixture of 2,6-dichloro-4-iodopyridine (8.50 g, 31.03 mmol), TEA (3.14g, 31.03 mmol) and morpholine (2.70 g, 30.99 mmol) was stirred for 2 hat 100° C. under nitrogen atmosphere. The resulting mixture was dilutedwith EtOAc (200 mL), washed with sat. NaHCO₃ (sat., 3×100 mL) andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with hexane/EtOAc (5/1) to afford4-(6-chloro-4-iodopyridin-2-yl)morpholine (4.28 g, 42%) as a whitesolid. MS ESI calculated for C₉H₁₀ClIN₂O [M+H]⁺, 324.95, found 324.95.¹H NMR (400 MHz, DMSO-d₆) δ 7.18 (d, J=0.8 Hz, 1H), 7.08 (d, J=0.8 Hz,1H), 3.67-3.65 (m, 4H), 3.47-3.45 (m, 4H).

Preparation 4B:N-(3-(2-chloro-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

A mixture of 4-(6-chloro-4-iodopyridin-2-yl)morpholine (2.00 g, 6.16mmol),N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(2.50 g, 6.16 mmol), Na₂CO₃ (1.96 g, 18.486 mmol) and Pd(dppf)Cl₂.CH₂Cl₂(0.50 g, 0.62 mmol) in DMF (40 mL) and H₂O (10 mL) was stirred at 60° C.for 2 h under N₂ atmosphere. The reaction was quenched with water (50mL) and extracted with EtOAc (3×100 mL). The combined organic layerswere washed with brine (3×50 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withPE/EtOAc (1/1) to affordN-(3-(2-chloro-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(2.00 g, 68%) as a brown solid. MS ESI calculated for C₂₃H₂₀ClF₃N₄O₂[M+H]⁺, 477.12; found 477.20. ¹H NMR (400 MHz, Chloroform-d) δ 8.94-8.87(m, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 7.60-7.47 (m, 2H),7.30 (s, 1H), 6.62 (s, 1H), 6.43 (s, 1H), 3.84-3.81 (m, 4H), 3.55-3.51(m, 4H), 2.28 (s, 3H).

Preparation 4C:N-[3-(2-[3-[(tert-butyldimethylsilyl)oxy]prop-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide

A mixture ofN-[3-[2-chloro-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(300 mg, 0.629 mmol), tert-butyldimethyl(prop-2-yn-1-yloxy)silane (214mg, 1.258 mmol), 2nd Generation XantPhos precatalyst (56 mg, 0.063mmol), XantPhos (36 mg, 0.063 mmol), TEA (191 mg, 1.887 mmol) and CuI (6mg, 0.031 mmol) in DMF (5 mL) was stirred at 90° C. for 16 h under N₂atmosphere. The reaction was quenched with water (50 mL) and extractedwith EtOAc (3×50 mL). The combined organic layers were washed with brine(3×20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure. The residue was purified byPrep-TLC with PE/EtOAc (1/1) to affordN-[3-(2-[3-[(tert-butyldimethylsilyl)oxy]prop-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(350 mg, 91%) as brown oil. MS ESI calculated for C₃₂H₃₇F₃N₄O₃Si [M+H]⁺,611.26, found 611.15. ¹H NMR (400 MHz, Chloroform-d) δ 8.75 (d, J=5.0Hz, 1H), 7.95-7.93 (m, 2H), 7.81-7.76 (m, 1H), 7.46 (dd, J=8.4, 2.4 Hz,1H), 7.30 (d, J=2.4 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.64 (d, J=1.2 Hz,1H), 6.35 (d, J=1.2 Hz, 1H), 4.38 (s, 2H), 3.65-3.61 (m, 4H), 3.42-3.35(m, 4H), 2.11 (s, 3H), 0.77 (s, 9H), 0.01 (s, 6H).

Example 4:N-[3-[2-(3-hydroxyprop-1-yn-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide

A mixture ofN-[3-(2-[3-[(tert-butyldimethylsilyl)oxy]prop-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl)-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(400 mg, 0.66 mmol) in TBAF (5 mL, 1 M in THF) was stirred for 1 h atroom temperature. The reaction was quenched with water (20 mL). Theresulting mixture was extracted with EtOAc (3×50 mL). The combinedorganic layers were washed with brine (3×20 mL), dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by Prep-TLC with PE/EtOAc (1/2). Thecrude product was purified by reverse flash chromatography with thefollowing conditions: Column: C18 Column 120 g; Mobile Phase A: water(10 mmol/L NH₄HCO₃), Mobile Phase B: CH₃CN; Flow rate: 60 mL/min;Gradient: 30% B to 60% B in 30 min; 254/220 nm to affordN-[3-[2-(3-hydroxyprop-1-yn-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(142 mg, 44%) as a light yellow solid. MS ESI calculated forC₂₆H₂₃F₃N₄O₃[M+H]⁺, 497.17, found 497.10. ¹H NMR (400 MHz, Chloroform-d)δ 8.92 (d, J=4.8 Hz, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 7.98 (d, J=4.4 Hz,1H), 7.61 (dd, J=8.4, 2.0 Hz, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.29 (d,J=9.2 Hz, 1H), 6.80 (s, 1H), 6.56 (s, 1H), 4.51 (s, 2H), 3.84-3.81 (m,4H), 3.57-3.55 (m, 4H), 2.27 (s, 3H). ¹⁹F NMR (376 MHz, Chloroform-d) δ−67.96 (3F).

Example 5:(3S)—N-[3-[2-(2-aminopyrimidin-4-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

Preparation 5A: 4-(4,6-dichloropyridin-2-yl)morpholine

A mixture of 2,4,6-trichloropyridine (29.20 g, 160.06 mmol), morpholine(14 mL, 160.06 mmol) and DIEA (28 mL, 215.72 mmol) in 1,4-dioxane (160mL) was stirred for 16 h at 85° C. The mixture was allowed to cool downto room temperature. The reaction was quenched with water (300 mL). Theresulting mixture was extracted with EtOAc (3×200 mL). The combinedorganic layers were washed with brine (300 mL), dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with EtOAc/PE (15/85) to afford4-(4,6-dichloropyridin-2-yl)morpholine (19.10 g, 51%) as an off-whitesolid. MS ESI calculated for C₉H₁₀Cl₂N₂O [M+H]⁺, 233.02, found 232.90.¹H NMR (400 MHz, Chloroform-d) δ 6.67 (d, J=1.2 Hz, 1H), 6.48 (d, J=1.2Hz, 1H), 3.83-3.76 (m, 4H), 3.56-3.49 (m, 4H).

Preparation 5B: tert-butylN-{3-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]prop-2-yn-1-yl}carbamate

A mixture of 4-(4,6-dichloropyridin-2-yl)morpholine (500 mg, 2.145mmol,), tert-butyl N-(prop-2-yn-1-yl)carbamate (666 mg, 4.290 mmol), TEA(1 mL,), DMF (5 mL), CuI (82 mg, 0.429 mmol) and Pd(PPh₃)₂Cl₂ (150 mg,0.215 mmol) was stirred for 16 h at 80° C. under nitrogen atmosphere.The resulting mixture was diluted with water (30 mL) and extracted withEtOAc (3×20 mL). The combined organic layers were washed with brine(2×20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with PE/EtOAc (5/4) to affordtert-butylN-{3-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]prop-2-yn-1-yl}carbamate(210 mg, 23%) as a yellow solid. MS ESI calculated forC₁₇H₂₂ClN₃O₃[M+H]⁺, 352.13, found 352.20. ¹H NMR (300 MHz, Chloroform-d)δ 6.81 (d, J=1.5 Hz, 1H), 6.59 (d, J=1.5 Hz, 1H), 4.18 (d, J=5.6 Hz,2H), 3.86-3.76 (m, 4H), 3.58-3.49 (m, 4H), 1.49 (s, 9H).

Preparation 5C: tert-butylN-[3-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)prop-2-yn-1-yl]carbamate

A mixture of tert-butylN-{3-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]prop-2-yn-1-yl}carbamate(220 mg, 0.625 mmol), K₃PO₄ (265.46 mg, 1.250 mmol),N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(279 mg, 0.688 mmol), THF (2 mL,), H₂O (0.2 mL) and 2nd GenerationXantPhos precatalyst (49 mg, 0.063 mmol) was stirred for 2 h at 80° C.under nitrogen atmosphere. The resulting mixture was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EtOAc/EtOH (4/3/1) to afford tert-butylN-[3-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)prop-2-yn-1-yl]carbamate(170 mg, 45%) as a white solid. MS ESI calculated forC₃₁H₃₂F₃N₅O₄[M+H]⁺, 596.24; found 596.15; ¹H NMR (300 MHz, Chloroform-d)δ 8.95 (d, J=5.2 Hz, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.97 (d, J=4.8 Hz,1H), 7.61 (s, 1H), 7.52 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.82 (d, J=1.2Hz, 1H), 6.56 (s, 1H), 4.26-4.15 (m, 2H), 3.85-3.81 (m, 4H), 3.62-3.58(m, 4H), 2.29 (s, 3H), 1.48 (s, 9H).

Example 5:N-{3-[2-(3-aminoprop-1-yn-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl}-2-(trifluoromethyl)pyridine-4-carboxamide

To a stirred mixture of tert-butylN-[3-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)prop-2-yn-1-yl]carbamate(170 mg, 0.285 mmol) in DCM (4 mL) was added TFA (1 mL) dropwise at 0°C. The reaction mixture was stirred for 30 min at room temperature. Theresulting mixture was concentrated under reduced pressure. The residuewas purified by reverse phase chromatography, eluted with CH₃CN/water(with 0.05% NH₄HCO₃) (10% to 50%) to affordN-{3-[2-(3-aminoprop-1-yn-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl}-2-(trifluoromethyl)pyridine-4-carboxamide(100.7 mg, 70%) as a white solid. MS ESI calculated forC₂₆H₂₄F₃N₅O₂[M+H]⁺, 496.19, found 496.25. ¹H NMR (300 MHz, Chloroform-d)δ 8.96 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.95-7.92 (m, 2H), 7.63-7.52 (m,2H), 7.33 (d, J=8.4 Hz, 1H), 6.82 (s, 1H), 6.54 (s, 1H), 3.86-3.83 (m,4H), 3.69 (s, 2H), 3.62-3.53 (m, 4H), 2.30 (s, 3H). ¹⁹F NMR (282 MHz,Chloroform-d) δ −67.93 (3F).

Example 6:N-(3-{2-[(3S)-3-aminobut-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

Preparation 6A: tert-butylN-[(2S)-4-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)but-3-yn-2-yl]carbamate

A mixture ofN-{3-[2-chloro-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl}-2-(trifluoromethyl)pyridine-4-carboxamide(500 mg, 1.048 mmol) and tert-butyl N-[(2S)-but-3-yn-2-yl]carbamate (355mg, 2.096 mmol) in DMF (10 mL), TEA (318 mg, 3.144 mmol), 2nd GenerationXantPhos precatalyst (93 mg, 0.105 mmol), XantPhos (61 mg, 0.105 mmol)and CuI (10 mg, 0.052 mmol) was stirred for 16 h at 80° C. undernitrogen atmosphere. The reaction was quenched by the addition of water(30 mL). The resulting mixture was extracted with EtOAc (3×50 mL). Thecombined organic layers were washed with brine (2×40 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EtOH/EtOAc (4/1/1) to afford tert-butylN-[(2S)-4-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)but-3-yn-2-yl]carbamate(489 mg, 76%) as an off-white solid. MS ESI calculated forC₃₂H₃₄F₃N₅O₄[M+H]⁺610.26; found 610.40. ¹H NMR (300 MHz, Chloroform-d) δ8.91 (d, J=4.8 Hz, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 8.00-7.94 (m, 1H),7.64 (d, J=8.1 Hz, 1H), 7.47 (s, 1H), 7.28 (d, J=8.1 Hz, 1H), 6.76 (d,J=1.2 Hz, 1H), 6.51 (s, 1H), 4.93 (s, 1H), 4.70 (s, 1H), 3.82-3.79 (m,4H), 3.56-3.53 (m, 4H), 2.25 (s, 3H), 1.48 (d, J=6.9 Hz, 3H), 1.43 (s,9H).

Example 6:N-(3-{2-[(3S)-3-aminobut-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

To a solution of tert-butylN-[(2S)-4-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)but-3-yn-2-yl]carbamate(489 mg, 0.802 mmol) and DCM (5 mL) was added TFA (1 mL). The resultingmixture was stirred for 1 h at room temperature. The resulting mixturewas concentration under reduced pressure. The residue was neutralized topH 8 with saturated NaHCO₃. The resulting mixture was extracted withEtOAc (3×30 mL). The combined organic layers were washed with brine(2×10 mL), dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure. The residue was purified byreverse flash chromatography with the following conditions: C18 column;mobile phase, CH₃CN in water (10 mmol/L NH₄HCO₃), 10% to 50%; detector,UV 254 nm to affordN-(3-{2-[(3S)-3-aminobut-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide(230 mg, 56%) as an off-white solid. MS ESI calculated for C₇H₂₆F₃N₅O₂[M+H]⁺510.20; found 510.20. ¹H NMR (400 MHz, Chloroform-d) δ 8.94 (d,J=4.8 Hz, 1H), 8.13 (s, 1H), 8.07 (s, 1H), 7.96 (d, J=4.8 Hz, 1H), 7.60(d, J=8.4 Hz, 1H), 7.50 (s, 1H), 7.31 (d, J=8.4 Hz, 1H), 6.80 (s, 1H),6.52 (s, 1H), 3.98 (s, 1H), 3.85-3.81 (m, 4H), 3.58-3.54 (m, 4H), 2.29(s, 3H), 1.48 (d, J=6.0 Hz, 3H). ¹⁹F NMR (376 MHz, Chloroform-d) δ−67.94 (3F).

Example 7:N-(3-{2-[(3R)-3-aminobut-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

Preparation 7A: tert-butylN-[(2R)-4-(4-{2-methyl-5-[2-trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)but-3-yn-2-yl]carbamate

A mixture ofN-{3-[2-chloro-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl}-2-(trifluoromethyl)pyridine-4-carboxamide(500 mg, 1.048 mmol) and tert-butyl N-[(2R)-but-3-yn-2-yl]carbamate (355mg, 2.096 mmol) in DMF (10 mL), TEA (318 mg, 3.144 mmol), 2nd GenerationXantPhos precatalyst (93 mg, 0.105 mmol), XantPhos (61 mg, 0.105 mmol)and CuI (10 mg, 0.052 mmol) was stirred for 16 h at 80° C. undernitrogen atmosphere. The reaction was quenched by the addition of water(30 mL). The resulting mixture was extracted with EtOAc (3×50 mL). Thecombined organic layers were washed with brine (2×40 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EtOH/EtOAc (4/1/1) to afford tert-butylN-[(2R)-4-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)but-3-yn-2-yl]carbamate(450 mg, 70%) as an off-white solid. MS ESI calculated forC₃₂H₃₄F₃N₅O₄[M+H]⁺610.26; found 610.30. ¹H NMR (300 MHz, Chloroform-d) δ8.94 (d, J=4.8 Hz, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 8.00-7.94 (m, 1H),7.64 (d, J=8.4 Hz, 1H), 7.47 (s, 1H), 7.28 (d, J=8.1 Hz, 1H), 6.76 (d,J=1.1 Hz, 1H), 6.51 (s, 1H), 4.93 (s, 1H), 4.74 (s, 1H), 3.86-3.82 (m,4H), 3.60-3.56 (m, 4H), 2.25 (s, 3H), 1.48 (d, J=6.9 Hz, 3H), 1.43 (s,9H).

Example 7:N-(3-{2-[(3R)-3-aminobut-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-2-(trifluoromethylpyridine-4-carboxamide

To a solution of tert-butylN-[(2R)-4-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)but-3-yn-2-yl]carbamate(450 mg, 0.738 mmol) and DCM (5 mL) was added TFA (1 mL). The resultingmixture was stirred for 1 h at room temperature. The resulting mixturewas concentration under reduced pressure. The residue was neutralized topH 8 with saturated NaHCO₃. The resulting mixture was extracted withEtOAc (3×30 mL). The combined organic layers were washed with brine(2×10 mL), dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure. The residue was purified byreverse flash chromatography with the following conditions: C18 column;mobile phase, CH₃CN in water (10 mmol/L NH₄HCO₃), 10% to 50%; detector,UV 254 nm to affordN-(3-{2-[(3R)-3-aminobut-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide(210 mg, 56%) as an off-white solid. MS ESI calculated for C₂₇H₂₆F₃N₅O₂[M+H]⁺510.20; found 510.20. ¹H NMR (400 MHz, Chloroform-d) δ 8.94 (d,J=4.8 Hz, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 7.99-7.93 (m, 1H), 7.60 (d,J=7.6 Hz, 1H), 7.50 (s, 1H), 7.31 (d, J=8.4 Hz, 1H), 6.81 (s, 1H), 6.52(s, 1H), 3.99 (s, 1H), 3.85-3.81 (m, 4H), 3.58-3.54 (m, 4H), 2.29 (s,3H), 1.48 (d, J=6.4 Hz, 3H). ¹⁹F NMR (376 MHz, Chloroform-d) δ −67.95(3F).

Example 8:N-(3-{2-[3-(dimethylamino)prop-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

Preparation 8A:{3-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]prop-2-yn-1-yl}dimethylamine

A mixture of 4-(4,6-dichloropyridin-2-yl)morpholine (300 mg, 1.287mmol), dimethyl(prop-2-yn-1-yl)amine (214 mg, 2.574 mmol), Pd(PPh₃)₂Cl₂(90 mg, 0.129 mmol) and CuI (49 mg, 0.257 mmol) in TEA (2 mL) and DMF(10 mL) was stirred for 2 h 80° C. under nitrogen atmosphere. Thereaction was quenched by the addition of water (30 mL). The resultingmixture was extracted with EtOAc (3×30 mL). The combined organic layerswere washed with brine (15 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withPE/EtOAc (1/1) to afford{3-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]prop-2-yn-1-yl}dimethylamine(261 mg, 73%) as a brown solid. MS ESI calculated for C₁₄H₁₉ClN₃O[M+H]⁺, 280.11, found 280.20. ¹H NMR (400 MHz, Chloroform-d) δ 6.81 (d,J=1.5 Hz, 1H), 6.55 (d, J=1.5 Hz, 1H), 3.81-3.77 (m, 4H), 3.53-3.49 (m,6H), 2.38 (s, 6H).

Example 8:N-(3-{2-[3-(dimethylamino)prop-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

A mixture of{3-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]prop-2-yn-1-yl}dimethylamine(160 mg, 0.572 mmol),N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(232 mg, 0.572 mmol), 2nd Generation XPhos Precatalyst (50 mg, 0.057mmol) and K₃PO₄ (243 mg, 1.144 mmol) in THF (2 mL) and H₂O (0.2 mL) wasstirred for 2 h at 80° C. under nitrogen atmosphere. The resultingmixture was concentrated under reduced pressure. The residue waspurified by reverse flash chromatography with the following conditions:C18 column; mobile phase, MeOH in water, 30% to 70%; detector, UV 254 nmto affordN-(3-{2-[3-(dimethylamino)prop-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide(117.2 mg, 39%) as a white solid. MS ESI calculated for C₂₈H₂₉F₃N₅O₂[M+H]⁺, 524.22; found 524.25. ¹H NMR (300 MHz, DMSO-d₆) δ 10.70 (s, 1H),9.01 (d, J=5.1 Hz, 1H), 8.39 (s, 1H), 8.21 (d, J=4.8 Hz, 1H), 7.79 (dd,J=8.1, 2.1 Hz, 1H), 7.66 (d, J=2.1 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H),6.81-6.79 (m, 2H), 3.73-3.69 (m, 4H), 3.53-3.47 (m, 6H), 2.26 (s, 9H).¹⁹F NMR (282 MHz, DMSO-d₆) δ −66.45 (3F).

Example 9:N-{4-methyl-3-[2-(morpholin-4-yl)-6-[3-(pyrrolidin-1-yl)prop-1-yn-1-yl]pyridin-4-yl]phenyl}-2-(trifluoromethyl)pyridine-4-carboxamide

Preparation 9A:4-{4-chloro-6-[3-(pyrrolidin-1-yl)prop-1-yn-1-yl]pyridin-2-yl}morpholine

A mixture of 4-(4,6-dichloropyridin-2-yl)morpholine (300 mg, 1.287mmol), 1-(prop-2-yn-1-yl)pyrrolidine (421 mg, 3.861 mmol), Pd(PPh₃)₂Cl₂(90 mg, 0.129 mmol) and CuI (49 mg, 0.257 mmol) in TEA (2 mL) and DMF(10 mL) was stirred for overnight at 80° C. under argon atmosphere. Thereaction was quenched by the addition of water (30 mL). The resultingmixture was extracted with EtOAc (3×30 mL). The combined organic layerswere washed with brine (15 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withCH₂Cl₂/MeOH (10/1) to afford4-{4-chloro-6-[3-(pyrrolidin-1-yl)prop-1-yn-1-yl]pyridin-2-yl}morpholine(85 mg, 21%) as a light yellow oil. MS ESI calculated for C₁₆H₂₀ClN₃O[M+H]⁺, 306.13, found 306.05. ¹H NMR (400 MHz, Chloroform-d) δ 6.83 (d,J=1.5 Hz, 1H), 6.57 (d, J=1.5 Hz, 1H), 3.83-3.79 (m, 4H), 3.69 (s, 2H),3.55-3.52 (m, 4H), 2.77-2.71 (s, 4H), 1.90-1.84 (m, 4H).

Example 9:N-{4-methyl-3-[2-(morpholin-4-yl)-6-[3-(pyrrolidin-1-yl)prop-1-yn-1-yl]pyridin-4-yl]phenyl}-2-(trifluoromethyl)pyridine-4-carboxamide

A mixture of4-{4-chloro-6-[3-(pyrrolidin-1-yl)prop-1-yn-1-yl]pyridin-2-yl}morpholine(80 mg, 0.262 mmol),N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(117 mg, 0.288 mmol), 2nd Generation Xphos Precatalyst (21 mg, 0.026mmol) and K₃PO₄ (111 mg, 0.524 mmol) in THF (2 mL) and H₂O (0.2 mL) wasstirred for 2 h at 80° C. under nitrogen atmosphere. The resultingmixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH(10/1). The crude product was purified by reverse flash chromatographywith the following conditions: C18 column; mobile phase, CH₃CN in water(10 mmol/L NH₄HCO₃), 60% to 80%; detector, UV 254 nm to affordN-{4-methyl-3-[2-(morpholin-4-yl)-6-[3-(pyrrolidin-1-yl)prop-1-yn-1-yl]pyridin-4-yl]phenyl}-2-(trifluoromethyl)pyridine-4-carboxamide(47 mg, 33%) as a white solid. MS ESI calculated for C₃₀H₃₀F₃N₅O₂[M+H]⁺,550.24, found 550.30. ¹H NMR (400 MHz, DMSO-d₆) δ 10.70 (s, 1H), 9.00(d, J=4.8 Hz, 1H), 8.37 (s, 1H), 8.20 (d, J=4.8 Hz, 1H), 7.76 (dd,J=8.4, 1.6 Hz, 1H), 7.64 (s, 1H), 7.34 (d, J=8.4 Hz, 1H), 6.79 (s, 1H),6.77 (s, 1H), 3.71-3.67 (m, 4H), 3.61 (s, 2H), 3.51-3.47 (m, 4H),2.59-2.55 (m, 4H), 2.24 (s, 3H), 1.73-1.69 (m, 4H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −66.46 (3F).

Example 10:N-(4-methyl-3-{2-[3-(methylamino)prop-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}phenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

Preparation 10A: tert-butyl N-methyl-N-(prop-2-yn-1-yl)carbamate

A mixture of tert-butyl N-(prop-2-yn-1-yl)carbamate (2.00 g, 12.89 mmol)in DMF (20 mL) and sodium hydride (0.46 g, 19.331 mmol) was stirred for1 h at 0° C. To this was added methyl iodide (3.66 g, 25.77 mmol)dropwise at 0° C. The resulting mixture was stirred for 2 h at roomtemperature. The reaction was quenched by the addition of water (100mL). The resulting mixture was extracted with EtOAc (3×150 mL). Thecombined organic layers were washed with brine (150 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EtOAc (10/1) to afford tert-butylN-methyl-N-(prop-2-yn-1-yl)carbamate (1.86 g, 85%) as a light yellowoil. ¹H NMR (400 MHz, Chloroform-d) δ 4.04 (s, 2H), 2.92 (s, 3H), 2.22(s, 1H), 1.47 (s, 9H).

Preparation 10B: tert-butylN-{3-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]prop-2-yn-1-yl}-N-methylcarbamate

A mixture of 4-(4,6-dichloropyridin-2-yl)morpholine (500 mg, 2.145mmol), tert-butyl N-methyl-N-(prop-2-yn-1-yl)carbamate (267 mg, 3.218mmol), Pd(PPh₃)₂Cl₂ (150 mg, 0.215 mmol) and CuI (82 mg, 0.429 mmol) inTEA (2 mL) and DMF (10 mL) was stirred for 2 h 80° C. under nitrogenatmosphere. The reaction was quenched by the addition of water (30 mL).The resulting mixture was extracted with EtOAc (3×30 mL). The combinedorganic layers were washed with brine (15 mL), dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with PE/EtOAc (1/1) to afford tert-butylN-{3-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]prop-2-yn-1-yl}-N-methylcarbamate(369 mg, 61%) as a yellow oil. MS ESI calculated for C₁₈H₂₅ClN₃O₃[M+H]⁺,366.15, found 366.20. ¹H NMR (400 MHz, Chloroform-d) δ 6.80 (s, 1H),6.56 (s, 1H), 4.32-4.23 (m, 2H), 3.82-3.75 (m, 4H), 3.55-3.48 (m, 4H),2.97 (s, 3H), 1.48 (s, 9H).

Preparation 10C: tert-butylN-methyl-N-[3-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)prop-2-yn-1-yl]carbamate

A mixture of tert-butylN-{3-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]prop-2-yn-1-yl}-N-methylcarbamate(200 mg, 0.547 mmol),N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(222 mg, 0.547 mmol), 2nd Generation XPhos Precatalyst (43 mg, 0.055mmol) and K₃PO₄ (232 mg, 1.094 mmol) in THF (2 mL) and H₂O (0.2 mL) wasstirred for 2 h at 80° C. under nitrogen atmosphere. The resultingmixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with PE/EtOAc (1/1)to afford tert-butylN-methyl-N-[3-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)prop-2-yn-1-yl]carbamate(208 mg, crude) as a brown solid. MS ESI calculated forC₃₂H₃₄F₃N₅O₄[M+H]⁺, 610.26, found 610.30.

Example 10:N-(4-methyl-3-{2-[3-(methylamino)prop-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}phenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

To a solution of tert-butylN-methyl-N-[3-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)prop-2-yn-1-yl]carbamate(200 mg, 0.328 mmol) and DCM (5 mL) was added TFA (1 mL). The resultingmixture was stirred for 1 h at room temperature. The mixture wasconcentrated under reduced pressure and then neutralized to pH 8 withsaturated NaHCO₃. The resulting mixture was extracted with EtOAc (3×30mL). The combined organic layers were washed with brine (2×10 mL), driedover anhydrous Na₂SO₄. After filtration, the filtrate was concentratedunder reduced pressure. The residue was purified by reverse flashchromatography with the following conditions: C18 column; mobile phase,CH₃CN in water (10 mmol/L NH₄HCO₃), 30% to 65%; detector, UV 254 nm toaffordN-(4-methyl-3-{2-[3-(methylamino)prop-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}phenyl)-2-(trifluoromethyl)pyridine-4-carboxamide(83.5 mg, 50%) as a yellow solid. MS ESI calculated for C₂₇H₂₆F₃N₅O₂[M+H]⁺, 510.20, found 510.30. ¹H NMR (300 MHz, DMSO-d₆) δ 10.69 (s, 1H),9.00 (d, J=5.1 Hz, 1H), 8.38 (s, 1H), 8.19 (d, J=5.1 Hz, 1H), 7.76 (dd,J=8.4, 2.1 Hz, 1H), 7.65 (d, J=2.1 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 6.78(s, 1H), 6.76 (s, 1H), 3.72-3.66 (m, 4H), 3.52-3.48 (m, 6H), 2.34 (s,3H), 2.24 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −66.50 (3F).

Example 11:N-{4-methyl-3-[2-(morpholin-4-yl)-6-{2-[(2R)-pyrrolidin-2-yl]ethynyl}pyridin-4-yl]phenyl}-2-(trifluoromethyl)pyridine-4-carboxamide

Preparation 11A: tert-butyl(2R)-2-[2-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)ethynyl]pyrrolidine-1-carboxylate

A mixture ofN-{3-[2-chloro-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl}-2-(trifluoromethyl)pyridine-4-carboxamide(300 mg, 0.629 mmol), TEA (191 mg, 1.887 mmol), tert-butyl(2R)-2-ethynylpyrrolidine-1-carboxylate (246 mg, 1.258 mmol), CuI (24mg, 0.126 mmol) and Pd(PPh₃)₂Cl₂ (44 mg, 0.063 mmol) in DMF (4 mL) wasstirred for 16 h at 80° C. under nitrogen atmosphere. The resultingmixture was diluted with water (50 mL). The resulting mixture wasextracted with EtOAc (3×30 mL). The combined organic layers were washedwith brine (3×30 mL), dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with PE/EtOAc (1/1)to afford tert-butyl(2R)-2-[2-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)ethynyl]pyrrolidine-1-carboxylate(200 mg, crude) as a light yellow solid; MS ESI calculated forC₃₄H₃₆F₃N₅O₄[M+H]⁺, 636.27; found 636.35.

Example 11:N-{4-methyl-3-[2-(morpholin-4-yl)-6-{2-[(2R)-pyrrolidin-2-yl]ethynyl}pyridin-4-yl]phenyl}-2-(trifluoromethyl)pyridine-4-carboxamide

A mixture of tert-butyl(2R)-2-[2-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)ethynyl]pyrrolidine-1-carboxylate(230 mg, 0.334 mmol) in DCM (4 mL) was added TFA (1 mg) at 0° C. Thereaction mixture was stirred for 30 min at room temperature. Theresulting mixture was concentrated under reduced pressure. The residuewas purified by reverse phase chromatography, eluted with 65% CH₃CN inwater (with 0.05% NH₄HCO₃) to affordN-{4-methyl-3-[2-(morpholin-4-yl)-6-{2-[(2R)-pyrrolidin-2-yl]ethynyl}pyridin-4-yl]phenyl}-2-(trifluoromethyl)pyridine-4-carboxamide(95.1 mg, 49%) as a white solid. MS ESI calculated for C₂₉H₂₈F₃N₅O₂[M+H]⁺, 536.22; found 536.30. ¹H NMR (400 MHz, Chloroform-d) δ 8.94 (d,J=4.8 Hz, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 8.00-7.94 (m, 1H), 7.66-7.59(m, 1H), 7.47 (s, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.80 (s, 1H), 6.51 (s,1H), 4.13-4.09 (m, 1H), 3.84-3.81 (m, 4H), 3.59-3.52 (m, 4H), 3.21-3.14(m, 1H), 3.01-2.95 (m, 1H), 2.28 (s, 3H), 2.20-2.13 (m, 1H), 2.04-1.98(m, 2H), 1.87-1.78 (m, 1H). ¹⁹F NMR (376 MHz, Chloroform-d) δ −67.83(3F).

Examples 12 and 13:N-(4-methyl-3-{2-[(3R)-3-(methylamino)but-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}phenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

Preparation 12A: tert-butylN-[4-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]but-3-yn-2-yl]carbamate

A mixture of 4-(4,6-dichloropyridin-2-yl)morpholine (570 mg, 2.445 mmol)and tert-butyl N-(but-3-yn-2-yl)carbamate (828 mg, 4.891 mmol), TEA (1.5mL), DMF (6 mL), Pd(PPh₃)₂Cl₂ (172 mg, 0.245 mmol) and CuI (93 mg, 0.489mmol) was stirred for 16 h at 80° C. under argon atmosphere. Theresulting mixture was quenched with water (100 mL) and extracted withEtOAc (3×100 mL). The combined organic layers were washed with brine(2×50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with PE/EtOAc (5/1) to affordtert-butylN-[4-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]but-3-yn-2-yl]carbamate(850 mg, 95%) as a yellow solid. MS ESI calculated forC₁₈H₂₄ClN₃O₃[M+H]⁺, 366.15, found 366.20. ¹H NMR (400 MHz, Chloroform-d)δ 6.81 (s, 1H), 6.58 (s, 1H), 3.82-3.80 (m, 4H), 3.56-3.53 (m, 4H),1.51-1.44 (m, 12H).

Preparation 12B: tert-butylN-{4-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]but-3-yn-2-yl}-N-methylcarbamate

To a stirred mixture of tert-butylN-{4-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]but-3-yn-2-yl}carbamate(500 mg, 1.367 mmol) and NaH (82 mg, 2.050 mmol) in DMF (5 mL) was addedMel (388 mg, 2.734 mmol) at 0° C. The resulting mixture was stirred for3 h at room temperature. The mixture was quenched by the addition ofwater (20 mL). The resulting mixture was extracted with EtOAc (3×20 mL).The combined organic layers were washed with brine (20 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EtOAc (4/1) to afford tert-butylN-{4-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]but-3-yn-2-yl}-N-methylcarbamate(500 mg, 96%) as an orange oil. MS ESI calculated forC₁₉H₂₆ClN₃O₃[M+H]⁺, 380.17, found 380.10. ¹H NMR (400 MHz, Chloroform-d)δ 6.79 (d, J=1.6 Hz, 1H), 6.55 (d, J=1.6 Hz, 1H), 3.82-3.77 (m, 5H),3.53-3.50 (m, 4H), 2.91 (s, 3H), 1.47 (s, 9H), 1.45-1.42 (m, 3H).

Preparation 12C: tert-butylN-methyl-N-[4-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)but-3-yn-2-yl]carbamate

A mixture of tert-butylN-{4-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]but-3-yn-2-yl}-N-methylcarbamate(460 mg, 1.211 mmol),N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(492 mg, 1.211 mmol), 2^(nd) Generation Xphos precatalyst (95 mg, 0.121mmol) and K₃PO₄ (514 mg, 2.422 mmol) in THF (5 mL) and H₂O (0.5 mL) wasstirred for 16 h at 80° C. under nitrogen atmosphere. The reaction wasquenched by the addition of water (30 mL). The resulting mixture wasextracted with EtOAc (3×30 mL). The combined organic layers were washedwith brine (30 mL), dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with CH₂Cl₂/EtOAc(4/1) to afford tert-butylN-methyl-N-[4-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)but-3-yn-2-yl]carbamate(268 mg, 35%) as a light yellow oil. MS ESI calculated forC₃₃H₃₆F₃N₅O₄[M+H]⁺, 624.27, found 624.40. ¹H NMR (300 MHz, Chloroform-d)δ 8.92 (d, J=5.1 Hz, 1H), 8.37 (s, 1H), 8.16 (s, 1H), 7.97 (d, J=5.1 Hz,1H), 7.63 (d, J=8.1 Hz, 1H), 7.48 (s, 1H), 7.31 (d, J=7.8 Hz, 1H), 6.79(s, 1H), 6.52 (s, 1H), 5.40-5.26 (m, 1H), 3.84-3.80 (m, 4H), 3.56-3.52(m, 4H), 2.92 (s, 3H), 2.27 (s, 3H), 1.43 (d, J=6.9 Hz, 3H), 1.26 (s,9H).

Preparations 12D and 13D: tert-butylN-methyl-N-[(2R)-4-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)but-3-yn-2-yl]carbamateand tert-butylN-methyl-N-[(2S)-4-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)but-3-yn-2-yl]carbamate

Tert-butylN-methyl-N-[4-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)but-3-yn-2-yl]carbamate(280 mg, 0.449 mmol) was resolved by Prep-HPLC with the followingconditions Column: CHIRALPAK IE, 2×25 cm, 5 m; Mobile Phase A: Hexane(0.5% 2 M NH₃-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min;A:B=85:15; 220/254 nm, to give:

-   -   Preparation 12D as an off-white oil (90 mg, 32%), RT₁: 14.34        min. MS ESI calculated for C₃₃H₃₆F₃N₅O₄[M+H]⁺, 624.27, found        624.15.    -   Preparation 13D as an off-white oil (100 mg, 36%), RT₂: 19.93        min. MS ESI calculated for C₃₃H₃₆F₃N₅O₄[M+H]⁺, 624.27, found        624.15.

Examples 12 and 13:N-(4-methyl-3-{2-[(3R)-3-(methylamino)but-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}phenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

A mixture of Preparation 12D (90 mg, 0.144 mmol) in DCM (3 mL) and TFA(1 mL) was stirred for 2 h at room temperature. The resulting mixturewas concentrated under reduced pressure. The residue was basified to pH7 with saturated Na₂CO₃. The resulting mixture was extracted with EtOAc(3×50 mL). The combined organic layers were washed with brine (20 mL),dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by reverseflash chromatography with the following conditions: C18 column; mobilephase, CH₃CN in water (10 mmol/L NH₄HCO₃), 45% to 85% to Example 12 (24mg, 24%) as a white solid. MS ESI calculated for C₂₈H₂₈F₃N₅O₂[M+H]⁺,524.22, found 524.15. ¹H NMR (400 MHz, DMSO-d₆) δ 10.69 (s, 1H), 9.00(d, J=4.8 Hz, 1H), 8.37 (s, 1H), 8.20 (d, J=4.4 Hz, 1H), 7.77 (d, J=6.4Hz, 1H), 7.65 (s, 1H), 7.34 (d, J=8.4 Hz, 1H), 6.78 (s, 1H), 6.74 (s,1H), 3.74-3.68 (m, 4H), 3.58-3.55 (m, 1H), 3.53-3.48 (m, 4H), 2.36 (s,3H), 2.25 (s, 3H), 1.31 (d, J=6.8 Hz, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ−66.46 (3F).

A stirred mixture of Preparation 13D (100 mg, 0.160 mmol) in DCM (3 mL)and TFA (1 mL) was stirred for 2 h at room temperature. The resultingmixture was concentrated under reduced pressure. The residue wasbasified to pH 7 with saturated Na₂CO₃. The resulting mixture wasextracted with EtOAc (3×50 mL). The combined organic layers were washedwith brine (20 mL), dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by reverse flash chromatography with the following conditions:C18 column; mobile phase, CH₃CN in water (10 mmol/L NH₄HCO₃), 45% to 85%to give Example 13 (35 mg, 41%) as a white solid. MS ESI calculated forC₂₈H₂₈F₃N₅O₂[M+H]⁺, 524.22, found 524.15. ¹H NMR (400 MHz, DMSO-d₆) δ10.69 (s, 1H), 9.00 (d, J=4.8 Hz, 1H), 8.37 (s, 1H), 8.20 (d, J=5.2 Hz,1H), 7.76 (dd, J=8.0, 2.0 Hz, 1H), 7.66 (s, 1H), 7.34 (d, J=8.4 Hz, 1H),6.77 (s, 1H), 6.74 (s, 1H), 3.74-3.66 (m, 4H), 3.63-3.56 (m, 1H),3.51-3.47 (m, 4H), 2.36 (s, 3H), 2.25 (s, 3H), 1.31 (d, J=6.8 Hz, 3H).¹⁹F NMR (376 MHz, DMSO-d₆) −66.46 (3F).

Example 14:N-(3-{2-[(3S)-3-aminobut-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

Preparation 14A: tert-butyl(2S)-2-[2-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)ethynyl]pyrrolidine-1-carboxylate

A mixture ofN-{3-[2-chloro-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl}-2-(trifluoromethyl)pyridine-4-carboxamide(300 mg, 0.629 mmol), TEA (191 mg, 1.887 mmol), tert-butyl(2R)-2-ethynylpyrrolidine-1-carboxylate (246 mg, 1.258 mmol), CuI (24mg, 0.126 mmol) and Pd(PPh₃)₂Cl₂ (44 mg, 0.063 mmol) in DMF (4 mL) wasstirred for 16 h at 80° C. under nitrogen atmosphere. The resultingmixture was diluted with water (50 mL). The resulting mixture wasextracted with EtOAc (3×30 mL). The combined organic layers were washedwith brine (3×30 mL), dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with PE/EtOAc (6/4)to afford tert-butyl(2S)-2-[2-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)ethynyl]pyrrolidine-1-carboxylate(200 mg, crude) as a light yellow solid; MS ESI calculated forC₃₄H₃₆F₃N₅O₄[M+H]⁺, 636.27; found 636.75.

Example 14:N-(3-{2-[(3S)-3-aminobut-1-yn-1-yl]-6-(morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

A mixture of tert-butyl(2S)-2-[2-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)ethynyl]pyrrolidine-1-carboxylate(230 mg, 0.334 mmol) in DCM (4 mL) was added TFA (1 mg). The reactionmixture was stirred for 30 min at room temperature. The resultingmixture was concentrated under reduced pressure. The residue waspurified by reverse phase chromatography, eluted with 60% CH₃CN in water(with 0.05% NH₄HCO₃) to affordN-{4-methyl-3-[2-(morpholin-4-yl)-6-{2-[(2S)-pyrrolidin-2-yl]ethynyl}pyridin-4-yl]phenyl}-2-(trifluoromethyl)pyridine-4-carboxamide(71.1 mg, 38%) as a white solid. MS ESI calculated for C₂₉H₂₈F₃N₅O₂[M+H]⁺, 536.22; found 536.20. ¹H NMR (400 MHz, Chloroform-d) δ 8.94 (d,J=4.8 Hz, 1H), 8.15 (s, 2H), 7.97 (d, J=4.8 Hz, 1H), 7.64-7.62 (m, 1H),7.48 (s, 1H), 7.31 (d, J=8.4 Hz, 1H), 6.80 (s, 1H), 6.51 (s, 1H),4.14-4.10 (m, 1H), 3.85-3.81 (m, 4H), 3.59-3.52 (m, 4H), 3.20-3.15 (m,1H), 3.02-2.96 (m, 1H), 2.28 (s, 3H), 2.20-2.13 (m, 1H), 2.04-1.80 (m,3H). ¹⁹F NMR (376 MHz, Chloroform-d) −67.98 (3F).

Examples 15 and 16:N-{4-methyl-3-[2-(morpholin-4-yl)-6-[(3S)-4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)pyridin-4-yl]phenyl}-2-(trifluoromethyl)pyridine-4-carboxamideandN-{4-methyl-3-[2-(morpholin-4-yl)-6-[(3R)-4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl]pyridin-4-yl]phenyl}-2-(trifluoromethyl)pyridine-4-carboxamide

Preparation 15A:4-{4-chloro-6-2-(trimethylsilyl)ethynyl]pyridin-2-yl}morpholine

A mixture of 4-(4,6-dichloropyridin-2-yl)morpholine (2.00 g, 8.58 mmol),trimethylsilylacetylene (1.69 g, 17.16 mmol), Pd(PPh₃)₂Cl₂ (0.60 g, 0.86mmol), CuI (0.33 g, 1.72 mmol) in TEA (4 mL) and DMF (20 mL) was stirredfor 16 h at 80° C. under nitrogen atmosphere. The resulting mixture wasquenched with H₂O (30 mL) and extracted with EtOAc (3×30 mL). Thecombined organic layers were washed with brine (20 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EtOAc (5/1) to afford4-{4-chloro-6-[2-(trimethylsilyl)ethynyl]pyridin-2-yl}morpholine (1.71g, 68%) as light yellow oil. MS ESI calculated for C₁₄H₁₉ClN₂OSi [M+H]⁺,295.10, found 295.05. ¹H NMR (400 MHz, Chloroform-d) δ 6.87 (d, J=1.6Hz, 1H), 6.58 (d, J=1.6 Hz, 1H), 3.83-3.79 (m, 4H), 3.56-3.53 (m, 4H),0.28 (s, 9H).

Preparation 15B: 4-(4-chloro-6-ethynylpyridin-2-yl)morpholine

A solution of4-{4-chloro-6-[2-(trimethylsilyl)ethynyl]pyridin-2-yl}morpholine (1.71g, 5.80 mmol) and K₂CO₃ (1.60 g, 11.58 mmol) in MeOH (15 mL) was stirredfor 1 h at room temperature. The resulting mixture was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EtOAc (5/1) to afford4-(4-chloro-6-ethynylpyridin-2-yl)morpholine (1.23 g, 95%) as lightyellow oil. MS ESI calculated for C₁₁H₁₁ClN₂O [M+H]⁺, 223.06, found223.15. ¹H NMR (400 MHz, Chloroform-d) δ 6.88 (d, J=1.6 Hz, 1H), 6.62(d, J=1.6 Hz, 1H), 3.84-3.79 (m, 4H), 3.58-3.53 (m, 4H), 3.11 (s, 1H).

Preparation 15C:4-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]-1,1,1-trifluorobut-3-yn-2-one

To a solution of 4-(4-chloro-6-ethynylpyridin-2-yl)morpholine (1.00 g,4.49 mmol) in THE (40 mL) was added n-BuLi (2.2 mL, 34.34 mmol) dropwiseat −78° C. under nitrogen atmosphere. The resulting mixture was stirredfor 30 min at −78° C. under nitrogen atmosphere. A stirred solution ofmethyltrifluoroacetate (1.44 g, 11.23 mmol) and BF₃.Et₂O (1.52 g, 22.45mmol) in THE was added to above mixture dropwise at −78° C. undernitrogen atmosphere. The resulting mixture was stirred for 2 h at −78°C. under nitrogen atmosphere. The reaction was quenched with sat. NH₄Cl(20 mL). The resulting mixture was extracted with EtOAc (3×20 mL). Thecombined organic layers were washed with brine (20 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EtOAc (2/1) to afford4-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]-1,1,1-trifluorobut-3-yn-2-one(1.19 g, 83%) as a light yellow solid. MS ESI calculated forC₁₃H₁₀ClF₃N₂O₂ [M+H]⁺, 319.04, found 319.20. ¹H NMR (400 MHz,Chloroform-d) δ 7.04 (d, J=1.2 Hz, 1H), 6.74 (d, J=1.6 Hz, 1H),3.82-3.79 (m, 4H), 3.58-3.55 (m, 4H). ¹⁹F NMR (376 MHz, Chloroform-d) δ−77.79 (3F).

Preparation 15D:4-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]-1,1,1-trifluorobut-3-yn-2-ol

A mixture of4-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]-1,1,1-trifluorobut-3-yn-2-one(1.12 g, 3.51 mmol) and NaBH₄ (0.27 g, 7.03 mmol) in MeOH (10 mL) wasstirred for 1 h at room temperature. The resulting mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with PE/EtOAc (2/1) to afford4-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]-1,1,1-trifluorobut-3-yn-2-ol(600 mg, 53%) as a light yellow solid. MS ESI calculated forC₁₃H₁₂ClF₃N₂O₂ [M+H]⁺, 321.05, found 321.05. ¹H NMR (400 MHz,Chloroform-d) δ 6.88 (d, J=1.2 Hz, 1H), 6.63 (d, J=1.2 Hz, 1H),4.95-4.90 (m, 1H), 3.88-3.82 (m, 4H), 3.58-3.54 (m, 4H). ¹⁹F NMR (376MHz, Chloroform-d) δ −78.94 (3F).

Examples 15 and 16:N-{4-methyl-3-[2-(morpholin-4-yl)-6-[(3S)-4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)pyridin-4-yl]phenyl}-2-(trifluoromethyl)pyridine-4-carboxamideandN-{4-methyl-3-[2-(morpholin-4-yl)-6-[(3R)-4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl]pyridin-4-yl]phenyl}-2-(trifluoromethyl)pyridine-4-carboxamide

A mixture of4-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]-1,1,1-trifluorobut-3-yn-2-ol(400 mg, 1.247 mmol),N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(456 mg, 1.122 mmol), K₃PO₄ (529 mg, 2.494 mmol) and 2^(nd) GenerationXphos Precatalyst (986 mg, 0.125 mmol) in THF (10 mL) and H₂O (1 mL) wasstirred for 2 h at 80° C. under nitrogen atmosphere. The resultingmixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with PE/EtOAc(1/1). The crude product was purified by Prep-CHIRAL-HPLC with thefollowing conditions: Column: CHIRALPAK AD-H, 2×25 cm, 5 m; Mobile PhaseA: Hexane (0.5% 2M NH₃-MeOH), Mobile Phase B: IPA; Flow rate: 20 mL/min;A:B+85:15; 220/254 nm, to give:

Example 15: 191 mg (27%) as a white solid, RT₁:13.54 min. MS ESIcalculated for C₂₇H₂₂F₆N₄O₃ [M+H]⁺, 565.16, found 565.20. ¹H NMR (400MHz, DMSO-d₆) δ 10.70 (s, 1H), 9.00 (d, J=5.2 Hz, 1H), 8.37 (s, 1H),8.21 (d, J=5.2 Hz, 1H), 7.78-7.75 (m, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.36(d, J=8.4 Hz, 1H), 7.22 (d, J=7.2 Hz, 1H), 6.89 (s, 1H), 6.84 (s, 1H),5.34-5.27 (m, 1H), 3.72-3.68 (m, 4H), 3.54-3.50 (m, 4H), 2.25 (s, 3H).¹⁹F NMR (376 MHz, DMSO-d₆) δ −66.46 (3F), −77.41 (3F).

Example 16: 131 mg (19%) as a white solid, RT₂: 19.37 min. MS ESIcalculated for C₂₇H₂₂F₆N₄O₃[M+H]⁺, 565.16, found 565.20. ¹H NMR (400MHz, DMSO-d₆) δ 10.69 (s, 1H), 9.00 (d, J=4.8 Hz, 1H), 8.37 (s, 1H),8.20 (d, J=5.2 Hz, 1H), 7.78-7.75 (m, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.36(d, J=8.4 Hz, 1H), 7.22 (d, J=7.2 Hz, 1H), 6.88 (s, 1H), 6.83 (s, 1H),5.32-5.28 (m, 1H), 3.72-3.68 (m, 4H), 3.53-3.49 (m, 4H), 2.25 (s, 3H).¹⁹F NMR (376 MHz, DMSO-d₆) δ −61.71 (3F), −72.66 (3F).

Example 17:N-{3-[2-(3-amino-3-methylbut-1-yn-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl}-2-(trifluoromethyl)pyridine-4-carboxamide

Preparation 17A: tert-butyl N-(2-methylbut-3-yn-2-yl) carbamate

A mixture of 2-amine-2-methyl-3-butyn (2.00 g, 24.06 mmol), Boc₂O (6.30g, 28.87 mmol) and TEA (7.30 g, 72.17 mmol) in DCM (50 mL) was stirredfor 16 h at room temperature. The reaction was quenched by the additionof water (50 mL). The resulting mixture was extracted with DCM (3×30mL). The organic layers were washed with brine (30 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EtOAc (5/1) to afford tert-butylN-(2-methylbut-3-yn-2-yl) carbamate (3.20 g, 72%) as a white solid.C₁₀H₁₇NO₂, ¹H NMR (400 MHz, Chloroform-d) δ 4.70 (s, 1H), 1.60 (s, 6H),1.47 (s, 9H).

Preparation 17B: tert-butylN-{4-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]-2-methylbut-3-yn-2-yl}carbamate

A mixture of 4-(4,6-dichloropyridin-2-yl)morpholine (500 mg, 2.145mmol), tert-butyl N-(2-methylbut-3-yn-2-yl)carbamate (511 mg, 2.788mmol), Pd(PPh₃)₂Cl₂ (150 mg, 0.215 mmol) and CuI (82 mg, 0.429 mmol) inTEA (2 mL) and DMF (10 mL) was stirred for 16 h at 80° C. under nitrogenatmosphere. The resulting mixture was diluted with water (40 mL). Theresulting mixture was extracted with EtOAc (3×50 mL). The combinedorganic layers were washed with brine (40 mL), dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with PE/EtOAc (2/1) to afford tert-butylN-{4-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]-2-methylbut-3-yn-2-yl}carbamate(612 mg, 75%) as a white solid. MS ESI calculated forC₁₉H₂₆ClN₃O₃[M+H]⁺, 380.17; found 380.30. ¹H NMR (400 MHz, Chloroform-d)δ 6.81 (d, J=1.6 Hz, 1H), 6.55 (d, J=1.6 Hz, 1H), 4.81 (s, 1H),3.84-3.77 (m, 4H), 3.56-3.51 (m, 4H), 1.68 (s, 6H), 1.47 (s, 9H).

Preparation 17C: tert-butylN-[3-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)prop-2-yn-1-yl]carbamate

A mixture of tert-butylN-{4-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]-2-methylbut-3-yn-2-yl}carbamate(100 mg, 0.263 mmol),N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(107 mg, 0.263 mmol), 2^(n) Generation XPhos Precatalyst (21 mg, 0.026mmol) and K₃PO₄ (112 mg, 0.526 mmol) in THF (2 mL) and H₂O (0.4 mL) wasstirred for 2 h at 80° C. under nitrogen atmosphere. The resultingmixture was diluted with water (20 mL). The resulting mixture wasextracted with EtOAc (3×20 mL). The combined organic layers were washedwith brine (10 mL), dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by Prep-TLC with DCM/MeOH (10/1) to afford tert-butylN-[2-methyl-4-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)but-3-yn-2-yl]carbamate(130 mg, 79%) as a white solid. MS ESI calculated forC₃₃H₃₆F₃N₅O₄[M+H]⁺, 624.27; found 624.35. ¹H NMR (400 MHz, Chloroform-d)δ 8.94 (d, J=4.8 Hz, 1H), 8.36 (s, 1H), 8.20 (s, 1H), 8.02 (d, J=4.8 Hz,1H), 7.71 (d, J=8.4 Hz, 1H), 7.45 (s, 1H), 7.31 (s, 1H), 6.78 (s, 1H),6.52 (s, 1H), 4.86 (s, 1H), 3.84-3.80 (m, 4H), 3.58-3.54 (m, 4H), 2.27(s, 3H), 1.45 (s, 6H), 1.26 (s, 9H).

Example 17:N-{3-[2-(3-amino-3-methylbut-1-yn-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl}-2-(trifluoromethyl)pyridine-4-carboxamide

A mixture of tert-butylN-[2-methyl-4-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)but-3-yn-2-yl]carbamate(150 mg, 0.241 mmol) and TFA (3 mL) in DCM (3 mL) was stirred for 1 h atroom temperature. The resulting mixture was concentrated under reducedpressure. The residue was purified by reverse phase Flash chromatographywith the following conditions: Column: WelFlash TM C18-I, 20-40 μm, 120g; Eluent A: water (10 mmol/L NH₄HCO₃); Eluent B: CH₃CN; Gradient: 50%to 70% B; Flow rate: 60 mL/min; Detector: 220/254 nm to affordN-{3-[2-(3-amino-3-methylbut-1-yn-1-yl)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl}-2-(trifluoromethyl)pyridine-4-carboxamide(100 mg, 79%) as a light-yellow solid. MS ESI calculated forC₂₈H₂₈F₃N₅O₂[M+H]⁺, 524.22; found 524.20. ¹H NMR (300 MHz, DMSO-d₆) δ10.69 (s, 1H), 8.99 (d, J=5.1 Hz, 1H), 8.37 (s, 1H), 8.20 (d, J=5.1 Hz,1H), 7.78-7.74 (m, 1H), 7.65 (d, J=2.1 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H),6.75 (s, 1H), 6.69 (d, J=0.9 Hz, 1H), 3.71-3.68 (m, 4H), 3.50-3.47 (m,4H), 2.24 (s, 3H), 1.37 (s, 6H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −66.46(3F).

Example 18:N-(3-{2-[2-(1-aminocyclopropyl)ethynyl]-6-(morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

Preparation 18A: tert-butylN-(1-{2-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]ethynyl}cyclopropyl)carbamate

A mixture of 4-(4,6-dichloropyridin-2-yl)morpholine (350 mg, 1.502mmol), tert-butyl N-(1-ethynylcyclopropyl)carbamate (353 mg, 1.953mmol), Pd(PPh₃)₂Cl₂ (105 mg, 0.150 mmol) and CuI (57 mg, 0.300 mmol) inTEA (1 mL) and DMF (5 mL) was stirred for 4 h at 80° C. under nitrogenatmosphere. The reaction was quenched with water (30 ml). The resultingmixture was extracted with EtOAc (3×25 mL). The combined organic layerswere washed with brine (20 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withPE/EtOAc (2/1) to afford tert-butylN-(1-{2-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]ethynyl}cyclopropyl)carbamate(350 mg, 62%) as a light yellow solid. MS ESI calculated forC₁₉H₂₄ClN₃O₃[M+H]⁺, 378.15, found 378.05. ¹H NMR (400 MHz, Chloroform-d)δ 6.78 (s, 1H), 6.54 (d, J=1.6 Hz, 1H), 5.10 (s, 1H), 3.83-3.77 (m, 4H),3.54-3.49 (m, 4H), 1.49 (s, 9H), 1.37-1.34 (m, 2H), 1.24-1.20 (m, 2H).

Preparation 18B: tert-butylN-{1-[2-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)ethynyl]cyclopropyl}carbamate

A mixture of tert-butylN-(1-{2-[4-chloro-6-(morpholin-4-yl)pyridin-2-yl]ethynyl}cyclopropyl)carbamate(200 mg, 0.529 mmol),N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(193 mg, 0.476 mmol), 2^(nd) Generation Xphos Precatalyst (42 mg, 0.053mmol) and K₃PO₄ (225 mg, 1.058 mmol) in THF (5 mL) and H₂O (0.5 mL) wasstirred for 2 h at 80° C. under nitrogen atmosphere. The resultingmixture was concentrated under reduced pressure. The residue waspurified by Prep-TLC with PE/EtOAc (1/1) to afford tert-butylN-{1-[2-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)ethynyl]cyclopropyl}carbamate(160 mg, 49%) as a light yellow solid. MS ESI calculated forC₃₃H₃₄F₃N₅O₄[M+H]⁺, 622.26, found 622.35. ¹H NMR (400 MHz, Chloroform-d)δ 8.91 (d, J=4.8 Hz, 1H), 8.25 (s, 1H), 8.12-8.00 (m, 1H), 7.76 (s, 1H),7.38 (s, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.69 (s, 1H), 6.46 (s, 1H), 5.27(s, 1H), 3.82-3.78 (, 4H), 3.52-3.48 (m, 4H), 2.24 (s, 3H), 1.43 (s,9H), 1.19-1.18 (m, 2H), 0.93-0.81 (m, 2H). ¹⁹F NMR (376 MHz,Chloroform-d) δ −67.93 (3F).

Example 18:N-(3-{2-[2-(1-aminocyclopropyl)ethynyl]-6-(morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

A solution of tert-butylN-{1-[2-(4-{2-methyl-5-[2-(trifluoromethyl)pyridine-4-amido]phenyl}-6-(morpholin-4-yl)pyridin-2-yl)ethynyl]cyclopropyl}carbamate(150 mg, 0.241 mmol), DCM (2 mL) and TFA (0.5 mL) was stirred for 1 h atroom temperature. The resulting mixture was concentrated under reducedpressure. The residue product was purified by reverse phase flash withthe following conditions: Column: Spherical C18, 20˜40 μm, 120 g; MobilePhase A: water (10 mM NH₄HCO₃); Mobile Phase B: CH₃CN; Flow rate: 60mL/min; Gradient: 40% to 60% B, Detector: 220 nm to affordN-(3-{2-[2-(1-aminocyclopropyl)ethynyl]-6-(morpholin-4-yl)pyridin-4-yl}-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide(45 mg, 36%) as a white solid. MS ESI calculated for C₂₈H₂₆F₃N₅O₂[M+H]⁺,522.20, found 522.20. ¹H NMR (400 MHz, DMSO-d₆) δ 10.68 (s, 1H), 9.00(d, J=4.8 Hz, 1H), 8.37 (s, 1H), 8.20 (d, J=4.8 Hz, 1H), 7.75 (d, J=8.4Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 6.74 (s, 1H),6.69 (s, 1H), 3.70-3.67 (m, 4H), 3.49-3.46 (m, 4H), 2.23 (s, 3H),0.96-0.94 (m, 2H), 0.88-0.85 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ−66.46 (3F).

The following compounds in Table 3 were prepared using proceduressimilar to those described in Example 18 using appropriate startingmaterials.

TABLE 3 Exact Mass Entry Structure IUPAC Name [M + H]⁺ 19

N-(3-{6-[(3S)-3- aminobut-1-yn-1- yl]-5-(morpholin- 4-yl)pyridin-3-yl}-4-methylphenyl)- 2-(trifluoromethyl)- pyridine-4-carbox- amide Calc'd510.20, found 510.25 20

N-(3-{6-[(3R)-3- aminobut-1-yn-1- yl]-5-(morpholin- 4-yl)pyridin-3-yl}-4-methylphenyl)-2- (trifluoromethyl)- pyridine-4-carbox- amide Calc'd508.20, found 508.20

Example 21:N-(3-{6-[(3R)-3-Hydroxybut-1-yn-1-yl]-5-(morpholin-4-yl)pyridin-3-yl}-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

Step 1:N-(3-{6-[(3R)-3-Hydroxybut-1-yn-1-yl]-5-(morpholin-4-yl)pyridin-3-yl}-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

To a stirred mixture of(2R)-4-[5-chloro-3-(morpholin-4-yl)pyridin-2-yl]but-3-yn-2-ol (150 mg,0.562 mmol),N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(206 mg, 0.506 mmol) in THF (1 mL) and H₂O (0.1 mL) were added K₃PO₄(239 mg, 1.124 mmol) and 2^(nd) Generation X-Phos precatalyst (44 mg,0.056 mmol). The reaction mixture was stirred for 16 h at 80° C. undernitrogen atmosphere. The resulting mixture was quenched with water (50mL). The resulting mixture was extracted with EtOAc (3×50 mL). Thecombined organic layers was washed with brine (30 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by reverse flashchromatography with the following conditions: column, C18 silica gel;mobile phase, CH₃CN in water (10 mmol/L NH₄HCO₃), 35% to 65% gradient in25 min. The fractions contained desired product were combined andconcentrated to affordN-(3-{6-[(3R)-3-hydroxybut-1-yn-1-yl]-5-(morpholin-4-yl)pyridin-3-yl}-4-methylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide(88 mg, 31%) as an off-white solid. MS ESI calculated for C₂₇H₂₅F₃N₄O₃[M+H]⁺, 511.19; found 511.30. ¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1H),9.00-8.99 (m, 1H), 8.37 (s, 1H), 8.21-8.15 (m, 2H), 7.79-7.76 (m, 1H),7.67-7.66 (m, 1H), 7.38-7.35 (m, 2H), 5.57-5.55 (m, 1H), 4.69-4.66 (m,1H), 3.79-3.77 (m, 4H), 3.21-3.19 (m, 4H), 2.25 (s, 3H), 1.42 (d, J=6.4Hz, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −66.45 (3F).

The following compounds in Table 4 were prepared using proceduressimilar to those described in Example 21 using appropriate startingmaterials.

TABLE 4 Exact Mass Entry Structure IUPAC Name [M + H]⁺ 22

N-3-{6-[(3S)-3- Hydroxy-but-1-yn-1- yl]-5-(morpholin-4-yl)pyridin-3-yl}-4- methylphenyl)-2- (trifluoromethyl)-pyridine-4-carbox- amide Calc'd 511.19, found 511.20 23

N-{3-[6-(3-Hydroxy- 3-methylbut-1-yn-1- yl)-5-(morpholin-4-yl)pyridin-3-yl]-4- methylphenyl}-2- (trifluoromethyl)-pyridine-4-carbox- amide Calc'd 525.20, found 525.35 24

N-{3-[6-(2-Cyclo- propylethynyl)-5- (morpholin-4-yl)- pyridin-3-yl]-4-methylphenyl}-2- (trifluoromethyl)- pyridine-4-carbox- amide Calc'd507.19, found 507.15 25

N-{4-Methyl-3-[5- (morpholin-4-yl)-6- (prop-1-yn-1-yl)-pyridin-3-yl]phenyl}- 2-(trifluoromethyl)- pyridine-4-carbox- amideCalc'd 481.18, found 481.35

Example 26:N-{3-[6-Ethynyl-5-(morpholin-4-yl)pyridin-3-yl]-4-methylphenyl}-2-(trifluoromethyl)pyridine-4-carboxamide

Step 1:N-{4-Methyl-3-[5-(morpholin-4-yl)-6-[2-(trimethylsilyl)ethynyl]pyridin-3-yl]phenyl}-2-(trifluoromethyl)pyridine-4-carboxamide

To a stirred mixture of4-{5-chloro-2-[2-(trimethylsilyl)ethynyl]pyridin-3-yl}morpholine (200mg, 0.678 mmol),N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide(248 mg, 0.610 mmol) and 2nd Generation XPhos precatalyst (53 mg, 0.068mmol) in THF (2 mL) and H₂O (0.2 mL) was added K₃PO₄ (432 mg, 2.034mmol). The reaction mixture was stirred for 2 h at 80° C. under nitrogenatmosphere. The reaction was quenched with water (50 mL). The resultingmixture was extracted with EA (2×50 mL). The combined organic layers waswashed with brine (50 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withPE/EA (1/1). The fractions contained desired product were combined andconcentrated to affordN-{4-methyl-3-[5-(morpholin-4-yl)-6-[2-(trimethylsilyl)ethynyl]pyridin-3-yl]phenyl}-2-(trifluoromethyl)pyridine-4-carboxamide(143 mg, 39%) as an off-white solid. MS ESI calculated forC₂₈H₂₉F₃N₄O₂Si [M+H]⁺, 539.20, found 539.20.

Step 2:N-{3-[6-Ethynyl-5-(morpholin-4-yl)pyridin-3-yl]-4-methylphenyl}-2-(trifluoromethyl)pyridine-4-carboxamide

To a stirred mixture ofN-{4-methyl-3-[5-(morpholin-4-yl)-6-[2-(trimethylsilyl)ethynyl]pyridin-3-yl]phenyl}-2-(trifluoromethyl)pyridine-4-carboxamide(93 mg, 0.173 mmol) in MeOH (1.3 mL) was added K₂CO₃ (48 mg, 0.346mmol). The reaction mixture was stirred for 2 h at room temperature. Theresulting mixture was quenched with water (10 mL) and extracted with EA(2×10 mL). The combined organic layers was washed with brine (5 mL),dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with PE/EA/EtOH (4/3/1). The fractionscontained desired product were combined and concentrated to affordN-{3-[6-ethynyl-5-(morpholin-4-yl)pyridin-3-yl]-4-methylphenyl}-2-(trifluoromethyl)pyridine-4-carboxamide(20 mg, 24%) as an off-white solid. MS ESI calculated forC₂₅H₂₁F₃N₄O₂[M+H]⁺, 467.17; found 467.30. ¹H NMR (400 MHz, Chloroform-d)δ 8.94 (d, J=5.2 Hz, 1H), 8.37 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 8.16 (s,1H), 8.00 (d, J=4.8 Hz, 1H), 7.73-7.70 (m, 1H), 7.55 (d, J=2.0 Hz, 1H),7.36 (d, J=8.4 Hz, 1H), 7.28-7.27 (m, 1H), 3.93-3.91 (m, 4H), 3.55 (s,1H), 3.30-3.28 (m, 4H), 2.29 (s, 3H). ¹⁹F NMR (376 MHz, Chloroform-d) δ−68.01 (3F).

Example 27:6-Tert-butyl-N-{4-methyl-3-[5-(morpholin-4-yl)-6-(prop-1-yn-1-yl)pyridin-3-yl]phenyl}pyrimidine-4-carboxamide

Step 1:4-Methyl-3-[5-(morpholin-4-yl)-6-(prop-1-yn-1-yl)pyridin-3-yl]aniline

To a stirred mixture of4-[5-chloro-2-(prop-1-yn-1-yl)pyridin-3-yl]morpholine (1.16 g, 4.901mmol), 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(1.23 g, 4.901 mmol), K₃PO₄ (2.08 g, 9.802 mmol) in THE (10 mL), H₂O (1mL) was added XPhos palladium(II) biphenyl-2-amine chloride (0.39 g,0.490 mmol). The reaction mixture was stirred for 2 h at 80° C. undernitrogen atmosphere. The mixture was allowed to cool down to roomtemperature. The reaction was quenched with water (50 mL). The resultingmixture was extracted with EtOAc (3×50 mL). The combined organic layerswere washed with brine (2×80 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withPE/EA/EtOH (4/3/1). The fractions contained desired product werecombined and concentrated to afford4-methyl-3-[5-(morpholin-4-yl)-6-(prop-1-yn-1-yl)pyridin-3-yl]aniline(1.10 g, 68%) as a light brown solid. MS ESI calculated for C₁₉H₂₁N₃O[M+H]⁺, 308.17, found 308.17.

Step 2:6-Tert-butyl-N-{4-methyl-3-[5-(morpholin-4-yl)-6-(prop-1-yn-1-yl)pyridin-3-yl]phenyl}pyrimidine-4-carboxamide

To a stirred solution of4-methyl-3-[5-(morpholin-4-yl)-6-(prop-1-yn-1-yl)pyridin-3-yl]aniline(80 mg, 0.260 mmol), 6-tert-butylpyrimidine-4-carboxylic acid (47 mg,0.260 mmol) and HATU (148 mg, 0.390 mmol) in CH₃CN (1 mL) was added TEA(105 mg, 1.040 mmol) dropwise at room temperature under nitrogenatmosphere. The resulting mixture was stirred for 16 h at roomtemperature under nitrogen atmosphere. The reaction was quenched by theaddition of water (20 mL) at room temperature. The resulting mixture wasextracted with EtOAc (3×30 mL). The combined organic layers was washedwith brine (2×20 mL), dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by Prep-TLC (PE/EA/EtOH (8/3/1)) to afford the crude product.The residue was purified by reverse flash chromatography with thefollowing conditions: column, C18 silica gel; mobile phase, CH₃CN inwater (10 mmol NH₄HCO₃), 35% to 95% gradient in 15 min; detector, UV 254nm. The fractions contained desired product were combined andconcentrated to afford6-tert-butyl-N-{4-methyl-3-[5-(morpholin-4-yl)-6-(prop-1-yn-1-yl)pyridin-3-yl]phenyl}pyrimidine-4-carboxamide(55 mg, 45%) as an off-white solid. MS ESI calculated for C₂₈H₃₁N₅O₂[M+H]⁺, 470.25, found 470.20. ¹H NMR (400 MHz, Chloroform-d) δ 9.96 (s,1H), 9.22 (s, 1H), 8.26-8.24 (m, 2H), 7.75-7.73 (m, 1H), 7.69 (s, 1H),7.36-7.34 (d, J=8.2 Hz, 1H), 7.25 (s, 1H), 3.95-3.93 (m, 4H), 3.30-3.28(m, 4H), 2.29 (s, 3H), 2.22 (s, 3H), 1.44 (s, 9H).

Example 28:N-(4-methyl-3-(5-morpholino-6-((tetrahydro-2H-pyran-4-yl)ethynyl)pyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide

Preparation 28A: 4-(5-bromo-2-chloropyridin-3-yl)morpholine

To a solution of 5-bromo-2-chloropyridin-3-amine (25.0 g, 120.8 mmol) inDMF (500 mL) was added NaH (12.0 g, 60%, 302.0 mmol) at ice-bathtemperature and the reaction was stirred for 30 min. The reaction wasadded 1-bromo-2-(2-bromoethoxy)ethane (30.1 g, 130.0 mmol) at ice-bathtemperature and the reaction was stirred at 80° C. for 3h. The reactionwas quenched with water (1000 ml). The mixture was filtered, washed withH₂O (200 mL) and PE/EA (30 mL, 3/1) to afford4-(5-bromo-2-chloropyridin-3-yl)morpholine (26.8 g, 80%) as a yellowsolid. MS ESI calculated for C₉H₁₀BrClN₂O [M+H]⁺, 277.97, found 278.00.

Preparation 28B:N-(3-(6-chloro-5-morpholinopyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

A mixture of 4-(5-bromo-2-chloropyridin-3-yl)morpholine (2.0 g, 7.19mmol),N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(2.9 g, 7.19 mmol), Pd(dppf)Cl₂ (292 mg, 0.40 mmol) and Cs₂CO₃ (4.7 g,14.38 mmol) in dioxane (100 mL) and H₂O (20 mL) was stirred for 5h at80° C. under nitrogen atmosphere. To the resulting mixture was addedwater (100 mL), extracted with EA (200 mL). The organic layer was driedover Na₂SO₄, filtered, concentrated under reduced pressure. The residuewas purified by FCC with PE/EtOAc (3/1) to affordN-(3-(6-chloro-5-morpholinopyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(2.5 g, 75%) as a yellow solid. MS ESI calculated for C₂₃H₃₀ClF₃N₄O₂[M+H]⁺, 477.12, found 477.10.

Example 28:N-(4-methyl-3-(5-morpholino-6-((tetrahydro-2H-pyran-4-yl)ethynyl)pyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide

A mixture ofN-(3-(6-chloro-5-morpholinopyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(300 mg, 0.63 mmol), 4-ethynyltetrahydro-2H-pyran (280 mg, 2.52 mmol),Pd(PPh₃)₂Cl₂ (42 mg, 0.06 mmol), CuI (6 mg, 0.03 mmol) and TEA (190 mg,1.89 mmol) in DMF (10 mL) was stirred at 100° C. for 16 h under nitrogenatmosphere. The resulting mixture was filtered, concentrated underreduced pressure. The residue was purified by prep-HPLC to affordN-(4-methyl-3-(5-morpholino-6-((tetrahydro-2H-pyran-4-yl)ethynyl)pyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(150.8 mg, 43%) as a yellow solid. MS ESI calculated forC₃₃H₃₄F₃N₅O₄[M+H]⁺, 551.22, found 551.20. ¹H NMR (400 MHz, DMSO-d6) δ10.71 (s, 1H), 8.99 (d, J=5.2 Hz, 1H), 8.37 (s, 1H), 8.20 (dd, J=1.2,5.2 Hz, 1H), 8.13 (d, J=2.0 Hz, 1H), 7.77 (dd, J=2.4, 8.4 Hz, 1H), 7.65(d, J=2.4 Hz, 1H), 7.37-7.34 (m, 2H), 3.86-3.76 (m, 6H), 3.50-3.44 (m,2H), 3.20-3.18 (m, 4H), 3.01-2.99 (m, 1H), 2.24 (s, 3H), 1.91-1.87 (m,2H), 1.66-1.62 (m, 2H).

Example 29:5-(5-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-3-morpholinopyridin-2-yl)pent-4-ynoicacid

Preparation 29A: methyl5-(5-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-3-morpholinopyridin-2-yl)pent-4-ynoate

A mixture ofN-(3-(6-chloro-5-morpholinopyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(500 mg, 1.05 mmol), methyl pent-4-ynoate (472 mg, 4.21 mmol),Pd(PPh₃)₂Cl₂ (75 mg, 0.11 mmol), CuI (10 mg, 0.05 mmol) and TEA (0.41mL, 3.16 mmol) in DMF (20 mL) was stirred at 100° C. for 16 h undernitrogen atmosphere. The resulting mixture was filtered, concentratedunder reduced pressure. The residue was purified by prep-HPLC to afford5-(5-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-3-morpholinopyridin-2-yl)pent-4-ynoate(350 mg, 60%) as a yellow solid. MS ESI calculated forC₂₉H₂₇F₃N₄O₄[M+H]⁺, 553.20, found 553.20.

Example 29:5-(5-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-3-morpholinopyridin-2-yl)pent-4-ynoicacid

A solution of-(5-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-3-morpholinopyridin-2-yl)pent-4-ynoate(200 mg, 0.36 mmol) and NaOH (30 mg, 0.72 mmol) in H₂O (5 mL) and THF (5mL) was stirred at RT for 2 h. The resulting mixture was acidified to pH5 with 1N HCl, concentrated under reduced pressure. The residue waspurified by prep-HPLC to afford5-(5-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-3-morpholinopyridin-2-yl)pent-4-ynoicacid (150.3 mg, 77%) as a yellow solid. MS ESI calculated forC₂₈H₂₅F₃N₄O₄[M+H]⁺, 539.18, found 539.20. ¹H NMR (400 MHz, CD₃OD) δ 8.80(d, J=5.2 Hz, 1H), 8.20 (s, 1H), 8.03-7.97 (m, 2H), 7.61 (dd, J=2.0, 8.0Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.25 (d, J=8.0Hz, 1H), 3.80-3.78 (m, 4H), 3.17-3.14 (m, 4H), 2.73 (t, J=7.2 Hz, 2H),2.55 (t, J=7.2 Hz, 2H), 2.18 (s, 3H).

Example 30:N-(4-methyl-3-(5-morpholino-6-(pyrrolidin-3-ylethynyl)pyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide

Preparation 30A: tert-butyl3-((5-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-3-morpholinopyridin-2-yl)ethynyl)pyrrolidine-1-carboxylate

A mixture ofN-(3-(6-chloro-5-morpholinopyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(300 mg, 0.63 mmol), tert-butyl 3-ethynylpyrrolidine-1-carboxylate (490mg, 2.52 mmol), Pd(PPh₃)₂Cl₂ (60 mg, 0.063 mmol), CuI (24 mg, 0.12 mmol)and TEA (0.41 mL, 3.16 mmol) in DMF (20 mL) was stirred at 100° C. for16 h under nitrogen atmosphere. The resulting mixture was filtered,concentrated under reduced pressure. The residue was purified byprep-HPLC to afford tert-butyl3-((5-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-3-morpholinopyridin-2-yl)ethynyl)pyrrolidine-1-carboxylate(300 mg, 75%) as a yellow oil. MS ESI calculated for C₂₉H₂₇F₃N₄O₄[M+H]+, 636.27, found 636.20.

Preparation 30:N-(4-methyl-3-(5-morpholino-6-(pyrrolidin-3-ylethynyl)pyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide

To a solution of tert-butyl3-((5-(2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)-3-morpholinopyridin-2-yl)ethynyl)pyrrolidine-1-carboxylate(300 mg, 0.47 mmol) in DCM (5 mL) was added TFA (1 mL) at rt and thereaction mixture was stirred for 3h. The reaction mixture was thenconcentrated. The residue was dissolved in water (20 mL) and EA (20 mL),basified to pH 9 with sat. Na₂CO₃. The organic layer was dried overNa₂SO₄, filtered, and concentrated. The residue was purified byprep-HPLC to afford HCOOH salt ofN-(4-methyl-3-(5-morpholino-6-(pyrrolidin-3-ylethynyl)pyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(135 mg, 54%) as a white solid. MS ESI calculated for C₂₉H₂₈F₃N₅O₂[M+H]⁺, 536.22, found 536.20. ¹H NMR (400 MHz, CD₃OD) δ 8.90 (d, J=4.8Hz, 1H), 8.51 (brs, 1H), 8.29 (s, 1H), 8.15-8.11 (m, 2H), 7.71 (d, J=2.0Hz, 1H), 7.66-7.63 (m, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.35 (d, J=8.4 Hz,1H), 3.89-3.86 (m, 4H), 3.60-3.57 (m, 2H), 3.52-3.47 (m, 1H), 3.41-3.37(m, 2H), 3.29-3.24 (m, 4H), 2.45-2.41 (m, 1H), 2.27 (s, 3H), 2.24-2.19(m, 1H).

Example 31:N-(3-(6-((1-acetylpyrrolidin-3-yl)ethynyl)-5-morpholinopyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

To a solution ofN-(4-methyl-3-(5-morpholino-6-(pyrrolidin-3-ylethynyl)pyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(150 mg, 0.23 mmol) and DIEA (149 mg, 1.15 mmol) in DCM (10 mL) wasadded acetyl chloride (19 mg, 0.23 mmol) and stirred for 30 min at 0° C.The reaction mixture was diluted with water (10 mL) and extracted withDCM (10 mL*2). The combined organic layers were washed with brine (10mL), dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified by prep-HPLC to giveN-(3-(6-((1-acetylpyrrolidin-3-yl)ethynyl)-5-morpholinopyridin-3-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide(26.3 mg, 23%) as a white solid. MS ESI calculated forC₃₁H₃₀F₃N₅O₃[M+H]⁺, 578.23, found 578.30. ¹H NMR (400 MHz, CD₃OD) δ 8.78(d, J=5.2 Hz, 1H), 8.18 (s, 1H), 7.99-7.98 (m, 2H), 7.57-7.54 (m, 2H),7.31 (s, 1H), 7.21 (d, J=8.0 Hz, 1H), 3.82-3.79 (m, 1H), 3.77-3.75 (m,4H), 3.71-3.62 (m, 1H), 3.55-3.50 (m, 1H), 3.46-3.31 (m, 2H), 3.13-3.12(m, 4H), 2.30-2.15 (m, 1H), 2.13 (s, 3H), 2.11-2.03 (m, 1H), 2.01 (s,3H).

Example 32:N-(4-methyl-3-(6-((1-methylpyrrolidin-3-yl)ethynyl)-5-morpholinopyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide

A mixture ofN-(4-methyl-3-(5-morpholino-6-(pyrrolidin-3-ylethynyl)pyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(100 mg, 0.17 mmol), HCHO (33 mg, 32% in H₂O, 0.35 mmol), and NaBH₃CN(44 mg, 0.70 mmol) in MeOH (8 mL) was stirred at 30° C. for 16 h undernitrogen atmosphere. The reaction mixture was diluted with water (10 mL)and extracted with DCM (10 mL*2). The combined organic layers werewashed with brine (10 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by prep-HPLC to giveN-(4-methyl-3-(6-((1-methylpyrrolidin-3-yl)ethynyl)-5-morpholinopyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(42.1 mg, 44%) as a white solid. MS ESI calculated forC₃₀H₃₀F₃N₅O₂[M+H]⁺, 550.24, found 550.20. ¹H NMR (400 MHz, DMSO-d6) δ10.72 (s, 1H), 9.01 (d, J=4.8 Hz, 1H), 8.38 (s, 1H), 8.21 (d, J=4.4 Hz,1H), 8.14 (d, J=1.2 Hz, 1H), 7.80-7.77 (m, 1H), 7.67 (d, J=1.6 Hz, 1H),7.38-7.34 (m, 2H), 3.80-3.79 (m, 4H), 3.31-3.24 (m, 1H), 3.21-3.20 (m,4H), 2.89 (t, J=8.4 Hz, 1H), 2.62-2.52 (m, 2H), 2.48-2.44 (m, 1H), 2.30(s, 3H), 2.28 (s, 3H), 2.25-2.21 (m, 1H), 1.89-1.84 (m, 1H).

Example 33:N-(4-methyl-3-(6-((1-(methylsulfonyl)pyrrolidin-3-yl)ethynyl)-5-morpholinopyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide

To a solution ofN-(4-methyl-3-(5-morpholino-6-(pyrrolidin-3-ylethynyl)pyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(300 mg, 0.46 mmol) and DIEA (294 mg, 2.30 mmol) in DCM (10 mL) wasadded methanesulfonyl chloride (58 mg, 0.51 mmol) and stirred for a hourat 0° C. The reaction mixture was diluted with water (10 mL) andextracted with DCM (15 mL*2). The combined organic layers were washedwith brine (10 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified byprep-HPLC to giveN-(4-methyl-3-(6-((1-(methylsulfonyl)pyrrolidin-3-yl)ethynyl)-5-morpholinopyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide(106.4 mg, 38%) as a white solid. MS ESI calculated for C₃₀H₃₀F₃N₅O₄S[M+H]⁺, 614.20, found 614.20. ¹H NMR (400 MHz, DMSO_d6) δ 10.71 (s, 1H),9.00 (d, J=5.2 Hz, 1H), 8.38 (s, 1H), 8.20 (d, J=4.4 Hz, 1H), 8.14 (d,J=1.6 Hz, 1H), 7.78-7.76 (m, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.38-7.36 (m,2H), 3.78-3.76 (m, 4H), 3.68-3.64 (m, 1H), 3.48-3.36 (m, 3H), 3.28-3.24(m, 1H), 3.19-3.17 (m, 4H), 2.97 (s, 3H), 2.34-2.30 (m, 1H), 2.24 (s,3H), 2.05-2.00 (m, 1H).

Example 34:5-fluoro-2-isopropyl-N-(4-methyl-3-(5-morpholino-6-(prop-1-yn-1-yl)pyridin-3-yl)phenyl)isonicotinamide

Preparation 34A: methyl 5-fluoro-2-(prop-1-en-2-yl)isonicotinate

A mixture of methyl 2-bromo-5-fluoroisonicotinate (900 mg, 3.85 mmol),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (712 mg, 4.24mmol), Pd(Amphos)Cl₂ (272 mg, 0.0385 mmol) and K₂CO₃ (1.6 g, 11.6 mmol)in toluene (15 mL) and MeOH (10 mL) was stirred at 65° C. for 2 hoursunder nitrogen atmosphere. After cooled to rt, the resulting mixture wasfiltered, concentrated under reduced pressure. The residue was purifiedby column chromatography on silica gel (PE/EA=20/1) to afford methyl5-fluoro-2-(prop-1-en-2-yl)isonicotinate (510 mg, 68%) as a yellow oil.MS ESI calculated for C₁₀H₁₀FNO₂ [M+H]⁺, 196.07, found 196.00.

Preparation 34B: methyl 5-fluoro-2-isopropylisonicotinate

A mixture of methyl 5-fluoro-2-(prop-1-en-2-yl)isonicotinate (500 mg,2.565 mmol) and Pd/C (100 mg, 5%) in MeOH (20 mL) was stirred at rtunder 1 atm H2 for 2 h. The reaction mixture was filtered andconcentrated to give methyl 5-fluoro-2-isopropylisonicotinate (400 mg,44%) as a white solid. MS ESI calculated for C10H12FNO2 [M+H]⁺, 198.09found 198.00.

Preparation 34C: 5-fluoro-2-isopropylisonicotinic acid

A mixture of methyl 5-fluoro-2-(prop-1-en-2-yl)isonicotinate (200 mg,1.0 mmol) and LiOH.H2O (126 mg, 3.0 mmol) in THF (5 mL) and H2O (5 mL)was stirred at rt overnight. THF was removed under reduced pressure, theresidue was adjusted pH 3 and with 1N HCl, filtered to give5-fluoro-2-isopropylisonicotinic acid (100 mg, 54%) as a white solid. MSESI calculated for C₉H₁₀FNO₂ [M+H]⁺, 184.07 found 184.00.

Preparation 34D:5-fluoro-2-isopropyl-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide

A mixture of 5-fluoro-2-isopropylisonicotinic acid (100 mg, 0.54 mmol)and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (126mg, 0.54 mmol), HATU (227 mg, 0.59 mmol), DIEA (210 mg, 1.63 mmol) inDMF (5 mL) was stirred at rt overnight. The reaction mixture was dilutedwith water (10 mL) and extracted with EA (15 mL*2). The combined organiclayers were washed with brine (10 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (PE/EA=10/1) toafford5-fluoro-2-isopropyl-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide(170 mg, 79%) as a yellow oil. MS ESI calculated for C₂₂H₂₈BFN₂O₃[M+H]⁺, 399.22, found 399.20.

Preparation 34:5-fluoro-2-isopropyl-N-(4-methyl-3-(5-morpholino-6-(prop-1-yn-1-yl)pyridin-3-yl)phenyl)isonicotinamide

A mixture of5-fluoro-2-isopropyl-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide(170 mg, 0.43 mmol),4-(5-bromo-2-(prop-1-yn-1-yl)pyridin-3-yl)morpholine (109 mg, 0.39mmol), Pd(dppf)₂Cl₂ (29 mg, 0.039 mmol) and K₂CO₃ (108 mg, 0.78 mmol) indioxane (10 mL) and H₂O (2 mL) was stirred at 85° C. for 5 h undernitrogen atmosphere. The resulting mixture was filtered, concentratedunder reduced pressure. The residue was purified by Prep-HPLC to afford5-fluoro-2-isopropyl-N-(4-methyl-3-(5-morpholino-6-(prop-1-yn-1-yl)pyridin-3-yl)phenyl)isonicotinamide(99.1 mg, 54%) as a white solid. MS ESI calculated for C₂₈H₂₉FN₄O₂[M+H]⁺, 473.23, found 473.30. ¹H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H),8.05 (s, 1H), 7.63-7.55 (m, 3H), 7.38-7.30 (m, 2H), 3.87-3.85 (m, 4H),3.24-3.23 (m, 4H), 3.14-3.10 (m, 1H), 2.25 (s, 3H), 2.16 (s, 3H), 1.32(d, J=6.8 Hz, 6H).

The following compounds in Table 5 were prepared using proceduressimilar to those described in Example 28, 29, 30, 31, 32, 33 and 34using appropriate starting materials.

TABLE 5 Exact Mass Entry Structure IUPAC Name [M + H]⁺ 35

methyl 5-(5-(2- methyl-5-(2- (trifluoromethyl)- isonicotinamido)-phenyl)-3-morpho- lino-pyridin-2-yl)- pent-4-ynoate Calc'd 553.20; found553.20 36

N-(3-(6-((1-acetyl- azetidin-3-yl)- ethynyl)-5-morpho-linopyridin-3-yl)- 4-methylphenyl)- 2-(trifluoromethyl)- isonicotinamideCalc'd 564.21; found 564.20 37

N-(3-(6-(4-hydroxy- but-1-yn-1-yl)-5- morpholinopyridin- 3-yl)-4-methyl-phenyl)-2-(trifluoro- methyl)isonicotin- amide Calc'd 511.19; found511.20 38

N-(3-(6-((1-acetyl- piperidin-3-yl)- ethynyl)-5-morpho-linopyridin-3-yl)-4- methylphenyl)-2- (trifluoromethyl)- isonicotinamideCalc'd 592.25; found 592.20 39

N-(3-(6-((1-acetyl- piperidin-4-yl)ethyn- yl)-5-morpholino-pyridin-3-yl)-4- methylphenyl)-2- (trifluoromethyl)- isonicotinamideCalc'd 592.25; found 592.30 40

N-(3-(6-(azetidin-3- ylethynyl)-5-mor- pholinopyridin-3-yl)-4-methylphenyl)-2- (trifluoromethyl)- isonicotinamide Calc'd 522.20;found 522.20 41

N-(4-methyl-3-(6- ((1-methylazetidin- 3-yl)ethynyl)-5-morpholinopyridin- 3-yl)phenyl)-2- (trifluoromethyl)iso- nicotinamideCalc'd 536.22; found 536.20 42

N-(3-(6-(5-hydroxy- pent-1-yn-1-yl)-5- morpholinopyridin-3-yl)-4-methyl- phenyl)-2-(trifluoro- methyl)isonicotin- amide Calc'd525.20; found 525.20 43

N-(4-methyl-3-(6- ((1-methylpiperidin- 4-yl)ethynyl)-5-morpholinopyridin- 3-yl)phenyl)-2- (trifluoromethyl)- isonicotinamideCalc'd 564.25; found 564.30 44

N-(4-methyl-3-(6- ((1-(methylsulfon- yl)azetidin-3-yl)-ethynyl)-5-morpho- linopyridin-3-yl)- phenyl)-2-(trifluoro-methyl)isonicotin- amide Calc'd 600.18; found 600.20 45

N-(4-methyl-3-(5- morpholino-6-((tetra- hydrofuran-3-yl)-ethynyl)pyridin-3- yl)phenyl)-2-(tri- fluoromethyl)iso- nicotinamideCalc'd 537.20; found 537.20 46

N-(4-methyl-3-(6- ((1-(methylsulfonyl)-piperidin-3-yl)ethyn-yl)-5-morpholino- pyridin-3-yl)phenyl)-2-(trifluoromethyl)- isonicotinamide Calc'd 628.21; found 628.20 47

N-(4-methyl-3-(6- ((1-(methylsulfon- yl)piperidin-4-yl)-ethynyl)-5-morpho- linopyridin-3-yl)- phenyl)-2-(trifluoro-methyl)isonicotin- amide Calc'd 628.21; found 628.20 48

N-(3-(6-(3-acetamido- prop-1-yn-1-yl)-5- morpholinopyridin-3-yl)-4-methylphenyl)- 2-(trifluoromethyl)- isonicotinamide Calc'd 538.20;found 538.20 49

N-(4-methyl-3-(5- morpholino-6-(3- (2-oxopyrrolidin-1-yl)prop-1-yn-1-yl)- pyridin-3-yl)phenyl)- 2-(trifluoromethyl)-isonicotinamide Calc'd 564.21; found 564.20 50

N-(4-methyl-3-(5- morpholino-6-(3-(3- oxomorpholino)prop-1-yn-1-yl)pyridin-3- yl)phenyl)-2-(tri- fluoromethyl)iso- nicotinamideCalc'd 580.21; found 580.20 51

N-(4-methyl-3-(5- morpholino-6- (piperidin-3-yl- ethynyl)pyridin-3-yl)phenyl)-2-(tri- fluoromethyl)- isonicotinamide Calc'd 550.24; found550.20 52

N-(4-methyl-3-(6- ((1-methylpiperidin- 3-yl)ethynyl)-5-morpholinopyridin- 3-yl)phenyl)-2- (trifluoromethyl)iso- nicotinamideCalc'd 564.25; found 564.30 53

N-(3-(6-(4-hydroxy- 4-methylpent-1-yn- 1-yl)-5-morpholino-pyridin-3-yl)-4- methylphenyl)-2- (trifluoromethyl)iso- nicotinamideCalc'd 539.22; found 539.20 54

N-(4-methyl-3-(5- morpholino-6- (oxetan-3-ylethyn- yl)pyridin-3-yl)-phenyl)-2-(trifluoro- methyl)isonicotin- amide Calc'd 523.19; found523.20 55

N-(4-methyl-3-(6- ((4-methyltetra- hydro-2H-pyran-4- yl)ethynyl)-5-mor-pholinopyridin-3-yl)- phenyl)-2-(trifluoro- methyl)isonicotin- amideCalc'd 565.24; found 565.30 56

N-(3-(6-(4-methoxy- but-1-yn-1-yl)-5- morpholinopyridin- 3-yl)-4-methyl-phenyl)-2-(trifluoro- methyl)isonicotin- amide Calc'd 525.20; found525.20 57

N-(3-(6-(5-methoxy- pent-1-yn-1-yl)-5- morpholinopyridin-3-yl)-4-methyl- phenyl)-2-(trifluoro- methyl)isonicotin- amide Calc'd539.22; found 539.30 58

N-(4-methyl-3-(5- morpholino-6- (piperidin-4-yl- ethynyl)pyridin-3-yl)phenyl)-2-(tri- fluoromethyl)iso- nicotinamide Calc'd 550.24; found550.20

II. Biological Evaluation Example 1: Kinase Assay Protocol

Enzymatic BRAF and RAF1 Kinase Activity Determination:

Small molecule inhibition of the BRA and RAF kinases was measured usingADP-Glo assay. In the assay, ADP is converted to ATP in the presence oftest kinase and substrate, resulting in luciferase reaction andluminescent readout with light generated proportional to the relativekinase activity. Compounds diluted in DMSO were used in 10-point, 3-folddose curve for both assays. Final concentrations of 6 nM BRAF (CarnaBio,Cat. 09-122) or 3 nM RAF1 (CaraBio, Cat. 09-125) and 30 nM MEK1substrate (Millipore, Cat. 14-420) were incubated with 3 μM ATP, 10 mMMgCl2, 0.003% Brij-35, 2 mM DTT, 0.0500 BSA, 1 mM EGTA, and 50 mM HEPESfor 90 minutes at room temp prior to addition of ADP-Glo reagent(Promega, Cat. V9102) for 40 minutes, and detection reagent for 45minutes. Luminescence was read on an Envision plate reader (PerkinElmer)and percent remaining activity was used to calculate IC50 using afour-parameter fit model using Dotmatics Knowledge Solutions Studiescurve fitting (Dotmatics, Bishops Stortford, UK, CM23).

Representative data for exemplary compounds is presented in Table 6.

TABLE 6 Synthetic Chemistry Example RAF-1 IC₅₀ 1 B 2 B 3 B 4 B 5 B 6 B 7B 8 B 9 B 10 B 11 A 12 B 13 B 14 A 15 A 16 A 17 B 18 B 19 B 20 A 21 A 22A 23 A 24 A 25 A 26 B 27 B 28 A 29 B 30 B 31 B 32 A 33 A 34 A 35 B 36 A37 A 38 A 39 B 40 A 41 B 42 B 43 A 44 B 45 B 46 B 47 A 48 A 49 A 50 A 51B 52 B 53 A 54 B 55 B 56 A 57 B 58 A Note: Biochemical assay IC₅₀ dataare designated within the following ranges: A: ≤0.001 μM B: >0.001 μM to≤0.010 μM C: >0.010 μM to ≤0.100 μM D: >0.100 μM to ≤1 μM

III. Preparation of Pharmaceutical Dosage Forms Example 1: Oral Capsule

The active ingredient is a compound of Table 1, or a pharmaceuticallyacceptable salt or solvate thereof. A capsule for oral administration isprepared by mixing 1-1000 mg of active ingredient with starch or othersuitable powder blend. The mixture is incorporated into an oral dosageunit such as a hard gelatin capsule, which is suitable for oraladministration.

Example 2: Solution for Injection

The active ingredient is a compound of Table 1, or a pharmaceuticallyacceptable salt or solvate thereof, and is formulated as a solution insesame oil at a concentration of 50 mg-eq/mL.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

1.-41. (canceled)
 42. A compound, or pharmaceutically acceptable salt orsolvate thereof, having the structure of Formula (I):

wherein, X is N or C—H; R¹ is selected from H, optionally substitutedC1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl; R² is selectedfrom H, optionally substituted C1-C6 alkyl, or optionally substitutedC3-C7 cycloalkyl; or optionally, R¹ and R² join to form a ring; R³ isselected from H, —OH, —OR⁴, —NH₂, —NHR⁴, —N(R⁴)₂, optionally substitutedheterocyclyl, or optionally substituted heteroaryl; each R⁴ isindependently selected from optionally substituted C1-C6 alkyl,optionally substituted C1-C6 acyl or optionally, R² and R⁴ join to forma ring; and Z is an optionally substituted aryl or heteroaryl.
 43. Thecompound of claim 42, or pharmaceutically acceptable salt or solvatethereof, wherein X is N.
 44. The compound of claim 42, orpharmaceutically acceptable salt or solvate thereof, wherein X is C—H.45. The compound of claim 42, or pharmaceutically acceptable salt orsolvate thereof, wherein R¹ is H.
 46. The compound of claim 42, orpharmaceutically acceptable salt or solvate thereof, wherein R¹ isoptionally substituted C1-C6 alkyl.
 47. The compound of claim 46, orpharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted alkyl is substituted with at least one halogen.48. The compound claim 46, or pharmaceutically acceptable salt orsolvate thereof, wherein R¹ is CH₃.
 49. The compound of claim 47, orpharmaceutically acceptable salt or solvate thereof, wherein R¹ is CF₃.50. The compound of claim 42, or pharmaceutically acceptable salt orsolvate thereof, wherein R¹ is optionally substituted C3-C7 cycloalkyl.51. The compound claim 42, or pharmaceutically acceptable salt orsolvate thereof, wherein R² is H.
 52. The compound of claim 42, orpharmaceutically acceptable salt or solvate thereof, wherein R² isoptionally substituted C1-C6 alkyl.
 53. The compound of claim 42, orpharmaceutically acceptable salt or solvate thereof, wherein R² isoptionally substituted C3-C7 cycloalkyl.
 54. The compound of claim 42,or pharmaceutically acceptable salt or solvate thereof, wherein R¹ andR² join to form a ring.
 55. The compound of claim 42, orpharmaceutically acceptable salt or solvate thereof, wherein R³ is —OH.56. The compound of claim 42, or pharmaceutically acceptable salt orsolvate thereof, wherein R³ is —OR⁴, —NH₂, —NHR⁴, or —N(R⁴)₂.
 57. Thecompound of claim 42, or pharmaceutically acceptable salt or solvatethereof, wherein R³ is optionally substituted heterocyclyl.
 58. Thecompound of claim 42, or pharmaceutically acceptable salt or solvatethereof, wherein R³ is optionally substituted heteroaryl.
 59. Thecompound of claim 56, or pharmaceutically acceptable salt or solvatethereof, wherein R⁴ is optionally substituted C1-C6 alkyl.
 60. Thecompound of claim 56, or pharmaceutically acceptable salt or solvatethereof, wherein R⁴ is optionally substituted C1-C6 acyl.
 61. Thecompound of claim 56, or pharmaceutically acceptable salt or solvatethereof, wherein R² and R⁴ join to form a ring.
 62. The compound ofclaim 42, or pharmaceutically acceptable salt or solvate thereof,wherein Z is an optionally substituted aryl.
 63. The compound of claim62, or pharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted aryl is an optionally substituted phenyl.
 64. Thecompound of claim 63, or pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted phenyl is an optionallysubstituted 3-(trifluoromethyl)phenyl.
 65. The compound of claim 42, orpharmaceutically acceptable salt or solvate thereof, wherein Z is a3-(trifluoromethyl)phenyl.
 66. The compound of claim 42, orpharmaceutically acceptable salt or solvate thereof, wherein Z is anoptionally substituted heteroaryl.
 67. The compound of claim 66, orpharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted heteroaryl is an optionally substitutedsix-membered heteroaryl.
 68. The compound of claim 67, orpharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted six-membered heteroaryl is an optionallysubstituted pyridyl.
 69. The compound of claim 68, or pharmaceuticallyacceptable salt or solvate thereof, wherein the optionally substitutedpyridyl is an optionally substituted 2-(trifluoromethyl)pyrid-4-yl. 70.The compound of claim 42, or pharmaceutically acceptable salt or solvatethereof, wherein Z is a 2-(trifluoromethyl)pyrid-4-yl.
 71. Apharmaceutical composition comprising a compound, or pharmaceuticallyacceptable salt or solvate thereof, as described in claim 42, and apharmaceutically acceptable excipient.